@article{%a1.%Ybr,

title = {Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma},

author = {Chiarini F and Paganelli F and Balestra T and Capanni C and Fazio A and Manara MC and Landuzzi L and Petrini S and Evangelisti C and Lollini PL and Martelli AM and Lattanzi G and Scotlandi K},

url = {https://www.nature.com/articles/s41419-022-04729-5},

doi = {10.1038/s41419-022-04729-5},

year  = {2022},

date = {2022-05-30},

urldate = {2022-05-30},

journal = {Cell death & disease},

volume = {13},

issue = {4},

pages = {346},

abstract = {Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Ybvw,

title = {Assessment of the structural and functional characteristics of human mesenchymal stem cells associated with a prolonged exposure of morphine},

author = {Carano F and Teti G and Ruggeri A and Chiarini F and Giorgetti A and Mazzotti MC and Fais P and Falconi M},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478991/},

doi = {10.1038/s41598-021-98682-6},

year  = {2021},

date = {2021-10-28},

journal = {Scientific Reports},

volume = {11},

number = {1},

pages = {19248},

abstract = {The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Ybv_29,

title = {Assessment of the structural and functional characteristics of human mesenchymal stem cells associated with a prolonged exposure of morphine},

author = {Carano F and Teti G and Ruggeri A and Chiarini F and Giorgetti A and Mazzotti MC and Fais P and Falconi M},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478991/},

doi = {10.1038/s41598-021-98682-6},

year  = {2021},

date = {2021-09-28},

journal = {Scientific Reports},

volume = {11},

number = {1},

pages = {19248},

abstract = {The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Yb,

title = {Cellular senescence in vascular wall mesenchymal stromal cells, a possible contribution to the development of aortic aneurysm},

author = {Teti G and Chiarini F and Mazzotti E and Ruggeri A and Carano F and Falconi M},

url = {https://www.sciencedirect.com/science/article/pii/S0047637421000877?via%3Dihub},

doi = {10.1016/j.mad.2021.111515},

year  = {2021},

date = {2021-06-08},

journal = {Mechanisms of ageing and development},

volume = {197},

number = {111515},

abstract = {Cellular senescence is a hallmark of ageing and it plays a key role in the development of age-related diseases. Abdominal aortic aneurysm (AAA) is an age related degenerative vascular disorder, characterized by a progressive dilatation of the vascular wall and high risk of rupture over time. Nowadays, no pharmacological therapies are available and the understanding of the molecular mechanisms that lead to AAA onset and development are poorly defined. In this study we investigated the cellular features of senescence in vascular mesenchymal stromal cells, isolated from pathological (AAA - MSCs) and healthy (h - MSCs) segments of human abdominal aorta and their implication in impairing the vascular repair ability of MSCs. Cell proliferation, ROS production, cell surface area, the expression of cyclin dependent kinase inhibitors p21CIP1 and p16INK4a, the activation of the DNA damage response and a dysregulated autophagy showed a senescent state in AAA - MSCs compared to h-MSCs. Moreover, a reduced ability to differentiate toward endothelial cells was observed in AAA - MSCs. All these data suggest that the accumulation of senescent vascular MSCs over time impairs their remodeling ability during ageing. This condition could support the onset and development of AAA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__515,

title = {GSK-3: a multifaceted player in acute leukemias},

author = {Martelli AM and Evangelisti C and Paganelli F and Chiarini F and McCubrey JA},

url = {https://www.nature.com/articles/s41375-021-01243-z},

doi = {10.1038/s41375-021-01243-z},

year  = {2021},

date = {2021-04-14},

urldate = {2021-04-14},

journal = {Leukemia},

volume = {35},

number = {1829},

issue = {7},

pages = {1842},

abstract = {Glycogen synthase kinase 3 (GSK-3) consists of two isoforms (alpha and beta) that were originally linked to glucose metabolism regulation. However, GSK-3 is also involved in several signaling pathways controlling many different key functions in healthy cells. GSK-3 is a unique kinase in that its isoforms are constitutively active, while they are inactivated mainly through phosphorylation at Ser residues by a variety of upstream kinases. In the early 1990s, GSK-3 emerged as a key player in cancer cell pathophysiology. Since active GSK-3 promotes destruction of multiple oncogenic proteins (e.g., beta-catenin, c-Myc, Mcl-1) it was considered to be a tumor suppressor. Accordingly, GSK-3 is frequently inactivated in human cancer via aberrant regulation of upstream signaling pathways. More recently, however, it has emerged that GSK-3 isoforms display also oncogenic properties, as they up-regulate pathways critical for neoplastic cell proliferation, survival, and drug-resistance. The regulatory roles of GSK-3 isoforms in cell cycle, apoptosis, DNA repair, tumor metabolism, invasion, and metastasis reflect the therapeutic relevance of these kinases and provide the rationale for combining GSK-3 inhibitors with other targeted drugs. Here, we discuss the multiple and often conflicting roles of GSK-3 isoforms in acute leukemias. We also review the current status of GSK-3 inhibitor development for innovative leukemia therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Yb_67,

title = {The Combination of AHCC and ETAS Decreases Migration of Colorectal Cancer Cells, and Reduces the Expression of LGR5 and Notch1 Genes in Cancer Stem Cells: A Novel Potential Approach for Integrative Medicine},

author = {Paganelli F and Chiarini F and Palmieri A and Martinelli M and Sena P and Bertacchini J and Roncucci L and Cappellini A and Martelli AM and Bonucci M and Fiorentini C and Hammarberg Ferri I},

doi = {10.3390/ph14121325},

year  = {2021},

date = {2021-12-14},

journal = {Pharmaceuticals},

volume = {14},

number = {12},

pages = {1325},

abstract = {The AHCC standardized extract of cultured Lentinula edodes mycelia, and the standardized extract of Asparagus officinalis stem, trademarked as ETAS, are well known supplements with immunomodulatory and anticancer potential. Several reports have described their therapeutic effects, including antioxidant and anticancer activity and improvement of immune response. In this study we aimed at investigating the effects of a combination of AHCC and ETAS on colorectal cancer cells and biopsies from healthy donors to assess the possible use in patients with colorectal cancer. Our results showed that the combination of AHCC and ETAS was synergistic in inducing a significant decrease in cancer cell growth, compared with single agents. Moreover, the combined treatment induced a significant increase in apoptosis, sparing colonocytes from healthy donors, and was able to induce a strong reduction in migration potential, accompanied by a significant modulation of proteins involved in invasiveness. Finally, combined treatment was able to significantly downregulate LGR5 and Notch1 in SW620 cancer stem cell (CSC) colonospheres. Overall, these findings support the potential therapeutic benefits of the AHCC and ETAS combinatorial treatment for patients with colorectal cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_468,

title = {B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients? },

author = {Ratti S and Lonetti A and Follo MY and Paganelli F and Martelli AM and Chiarini F and Evangelisti C},

url = {https://www.mdpi.com/2072-6694/12/12/3498},

doi = {10.3390/cancers12123498},

year  = {2020},

date = {2020-01-01},

journal = {Cancers},

volume = {12},

number = {12},

pages = {E3498},

abstract = {B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients' outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_448,

title = {Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer.},

author = {Evangelisti C and Chiarini F and Paganelli F and Marmiroli S and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488919302435?via%3Dihub},

doi = {10.1016/j.bbamcr.2019.118635},

year  = {2020},

date = {2020-01-01},

journal = {Biochimica et biophysica acta. Molecular cell research},

volume = {1867},

number = {4},

pages = {118635},

abstract = {The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells. Copyright 2019 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_456,

title = {Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of MLL-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML},

author = {Lonetti A and Indio V and Laginestra MA and Tarantino G and Chiarini F and Astolfi A and Bertuccio SN and Martelli AM and Locatelli F and Pession A and Masetti R},

url = {https://www.mdpi.com/2072-6694/12/7/1972},

doi = {10.3390/cancers12071972},

year  = {2020},

date = {2020-01-01},

journal = {Cancers},

volume = {12},

number = {7},

pages = {E1972},

abstract = {Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_449,

title = {Lamin A and Prelamin A Counteract Migration of Osteosarcoma Cells},

author = {Evangelisti C and Paganelli F and Giuntini G and Mattioli E and Cappellini A and Ramazzotti G and Faenza I and Maltarello MC and Martelli AM and Scotlandi K and Chiarini F and Lattanzi G},

url = {https://www.mdpi.com/2073-4409/9/3/774},

doi = {10.3390/cells9030774},

year  = {2020},

date = {2020-01-01},

journal = {Cells},

volume = {9},

number = {3},

pages = {774},

abstract = {A type lamins are fundamental components of the nuclear lamina. Changes in lamin A expression correlate with malignant transformation in several cancers. However, the role of lamin A has not been explored in osteosarcoma (OS). Here, we wanted to investigate the role of lamin A in normal osteoblasts (OBs) and OS cells. Thus, we studied the expression of lamin A/C in OS cells compared to OBs and evaluated the effects of lamin A overexpression in OS cell lines. We show that, while lamin A expression increases during osteoblast differentiation, all examined OS cell lines express lower lamin A levels relative to differentiated OBs. The condition of low LMNA expression confers to OS cells a significant increase in migration potential, while overexpression of lamin A reduces migration ability of OS cells. Moreover, overexpression of unprocessable prelamin A also reduces cell migration. In agreement with the latter finding, OS cells which accumulate the highest prelamin A levels upon inhibition of lamin A maturation by statins, had significantly reduced migration ability. Importantly, OS cells subjected to statin treatment underwent apoptotic cell death in a RAS-independent, lamin A-dependent manner. Our results show that pro-apoptotic effects of statins and statin inhibitory effect on OS cell migration are comparable to those obtained by prelamin A accumulation and further suggest that modulation of lamin A expression and post-translational processing can be a tool to decrease migration potential in OS cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_94,

title = {Targeting Wnt/beta-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia.},

author = {Evangelisti C and Chiarini F and Cappellini A and Paganelli F and Fini M and Santi S and Martelli AM and Neri LM and Evangelisti C},

url = {https://onlinelibrary.wiley.com/doi/full/10.1002/jcp.29429},

doi = {10.1002/jcp.29429},

year  = {2020},

date = {2020-01-01},

journal = {Journal of cellular physiology},

volume = {235},

number = {6},

pages = {5413-5428},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the clonal transformation of T-cell precursors. Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/beta-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells. Notably, beta-catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T-ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β-catenin pathway through ICG-001, a CBP/beta-catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK-474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T-ALL cells. ICG-001 and ZSTK-474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/beta-catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/beta-catenin and PI3K/Akt/mTOR pathways in T-ALL settings. Copyrights 2020 Wiley Periodicals, Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_437,

title = {The Role Played by Wnt/beta-Catenin Signaling Pathway in Acute Lymphoblastic Leukemia.},

author = {Chiarini F and Paganelli F and Martelli AM and Evangelisti C},

url = {https://www.mdpi.com/1422-0067/21/3/1098},

doi = {10.3390/ijms21031098},

year  = {2020},

date = {2020-01-01},

journal = {International journal of molecular sciences},

volume = {21},

number = {3},

pages = {e1098},

abstract = {Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of ALL and toxic effects limit dose escalation of current chemotherapeutics. Therefore, the identification of novel targeted therapies to support conventional chemotherapy is required. The Wnt/β-catenin pathway is a conserved signaling axis involved in several physiological processes such as development, differentiation, and adult tissue homeostasis. As a result, deregulation of this cascade is closely related to initiation and progression of various types of cancers, including hematological malignancies. In particular, deregulation of this signaling network is involved in the transformation of healthy HSCs in leukemic stem cells (LSCs), as well as cancer cell multi-drug-resistance. This review highlights the recent findings on the role of Wnt/beta-catenin in hematopoietic malignancies and provides information on the current status of Wnt/beta-catenin inhibitors with respect to their therapeutic potential in the treatment of ALL.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_458,

title = {The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias.},

author = {Martelli AM and Paganelli F and Chiarini F and Evangelisti C and McCubrey JA},

url = {https://www.mdpi.com/2072-6694/12/2/333},

doi = {10.3390/cancers12020333},

year  = {2020},

date = {2020-01-01},

journal = {Cancers},

volume = {12},

number = {2},

pages = {e333},

abstract = {The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6alpha (ATF6alpha), and inositol-requiring enzyme-1alpha (IRE1alpha). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%u,

title = {Advances in understanding the mechanisms of evasive and innate resistance to mTOR inhibition in cancer cells.},

author = {Chiarini F and Evangelisti C and Lattanzi G and McCubrey JA and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488919300424?via%3Dihub},

doi = {10.1016/j.bbamcr.2019.03.013},

year  = {2019},

date = {2019-02-20},

journal = {Biochimica et biophysica acta. Molecular cell research},

volume = {1866},

number = {8},

pages = {1322-1337},

abstract = {The development of drug-resistance by neoplastic cells is recognized as a major cause of targeted therapy failure and disease progression. The mechanistic (previously mammalian) target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that acts as the catalytic subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. Both mTORC1 and mTORC2 play key roles in a variety of healthy cell types/tissues by regulating physiological anabolic and catabolic processes in response to external cues. However, a body of evidence identified aberrant activation of mTOR signaling as a common event in many human tumors. Therefore, mTOR is an attractive target for therapeutic targeting in cancer and this fact has driven the development of numerous mTOR inhibitors, several of which have progressed to clinical trials. Nevertheless, mTOR inhibitors have met with a very limited success as anticancer therapeutics. Among other reasons, this failure was initially ascribed to the activation of several compensatory signaling pathways that dampen the efficacy of mTOR inhibitors. The discovery of these regulatory feedback mechanisms greatly contributed to a better understanding of cancer cell resistance to mTOR targeting agents. However, over the last few years, other mechanisms of resistance have emerged, including epigenetic alterations, compensatory metabolism rewiring and the occurrence of mTOR mutations. In this article, we provide the reader with an updated overview of the mechanisms that could explain resistance of cancer cells to the various classes of mTOR inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_46,

title = {Age-Related Alterations Affecting the Chondrogenic Differentiation of Synovial Fluid Mesenchymal Stromal Cells in an Equine Model.},

author = {Mazzotti E and Teti G and Falconi M and Chiarini F and Barboni B and Mazzotti A and Muttini A},

url = {https://www.mdpi.com/2073-4409/8/10/1116},

doi = {10.3390/cells8101116},

year  = {2019},

date = {2019-02-14},

journal = {Cells},

volume = {8},

number = {10},

pages = {pii: E1116},

abstract = {Osteoarthritis is a degenerative disease that strongly correlates with age and promotes the breakdown of joint cartilage and subchondral bone. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stromal cells (MSCs) isolated from adult tissues. It seems that MSCs derived from synovial joint tissues exhibit superior chondrogenic ability, but their unclear distribution and low frequency actually limit their clinical application. To date, the influence of aging on synovial joint derived MSCs' biological characteristics and differentiation abilities remains unknown, and a full understanding of the mechanisms involved in cellular aging is lacking. The aim of this study was therefore to investigate the presence of age-related alterations in synovial fluid MSCs and their influence on the potential ability of MSCs to differentiate toward chondrogenic phenotypes. Synovial fluid MSCs, isolated from healthy equine donors from 3 to 40 years old, were cultured in vitro and stimulated towards chondrogenic differentiation for up to 21 days. An equine model was chosen due to the high degree of similarity of the anatomy of the knee joint to the human knee joint and as spontaneous disorders develop that are clinically relevant to similar human disorders. The results showed a reduction in cell proliferation correlated with age and the presence of age-related tetraploid cells. Ultrastructural analysis demonstrated the presence of morphological features correlated with aging such as endoplasmic reticulum stress, autophagy, and mitophagy. Alcian blue assay and real-time PCR data showed a reduction of efficiency in the chondrogenic differentiation of aged synovial fluid MSCs compared to young MSCs. All these data highlighted the influence of aging on MSCs' characteristics and ability to differentiate towards chondrogenic differentiation and emphasize the importance of considering age-related alterations of MSCs in clinical applications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_33,

title = {Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer.},

author = {Evangelisti C and Chiarini F and Paganelli F and Marmiroli S and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488919302435?via%3Dihub},

doi = {10.1016/j.bbamcr.2019.118635},

year  = {2019},

date = {2019-02-21},

journal = {Biochimica et biophysica acta. Molecular cell research},

volume = {1867},

number = {4},

pages = {118635},

abstract = {The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells. Copyright 2019 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_67,

title = {New advances in targeting aberrant signaling pathways in T-cell acute lymphoblastic leukemia.},

author = {Paganelli F and Lonetti A and Anselmi L and Martelli AM and Evangelisti C and Chiarini F},

url = {https://www.sciencedirect.com/science/article/pii/S2212492619300703?via%3Dihub},

doi = {10.1016/j.jbior.2019.100649},

year  = {2019},

date = {2019-03-06},

journal = {Advances in biological regulation},

volume = {74},

pages = {100649},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disorder characterized by malignant transformation of immature progenitors primed towards T-cell development. Over the past 15 years, advances in the molecular characterization of T-ALL have uncovered oncogenic key drivers and crucial signaling pathways of this disease, opening new chances for the development of novel therapeutic strategies. Currently, T-ALL patients are still treated with aggressive therapies, consisting of high dose multiagent chemotherapy. To minimize and overcome the unfavorable effects of these regimens, it is critical to identify innovative targets and test selective inhibitors of such targets. Major efforts are being made to develop small molecules against deregulated signaling pathways, which sustain T-ALL cell growth, survival, metabolism, and drug-resistance. This review will focus on recent improvements in the understanding of the signaling pathways involved in the pathogenesis of T-ALL and on the challenging opportunities for T-ALL targeted therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_68,

title = {Phospholipase C-beta1 interacts with cyclin E in adipose- derived stem cells osteogenic differentiation.},

author = {Ramazzotti G and Fiume R and Chiarini F and Campana G and Ratti S and Billi AM and Manzoli L and Follo MY and Suh PG and McCubrey J and Cocco L and Faenza I},

url = {https://www.sciencedirect.com/science/article/pii/S2212492618301520?via%3Dihub},

doi = {10.1016/j.jbior.2018.11.001},

year  = {2019},

date = {2019-01-19},

journal = {Advances in biological regulation},

volume = {71},

number = {1},

pages = {9},

abstract = {Adipose-derived stem cells (ADSCs) are multipotent mesenchymal stem cells that have the ability to differentiate into several cell types, including chondrocytes, osteoblasts, adipocytes, and neural cells. Given their easy accessibility and abundance, they became an attractive source of mesenchymal stem cells, as well as candidates for developing new treatments for reconstructive medicine and tissue engineering. Our study identifies a new signaling pathway that promotes ADSCs osteogenic differentiation and links the lipid signaling enzyme phospholipase C (PLC)-beta1 to the expression of the cell cycle protein cyclin E. During osteogenic differentiation, PLC-beta1 expression varies concomitantly with cyclin E expression and the two proteins interact. These findings contribute to clarify the pathways involved in osteogenic differentiation and provide evidence to develop therapeutic strategies for bone regeneration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%t,

title = {The Cutting Edge: The Role of mTOR Signaling in Laminopathies.},

author = {Chiarini F and Evangelisti C and Cenni V and Fazio A and Paganelli F and Martelli AM and Lattanzi G},

doi = {10.3390/ijms20040847},

year  = {2019},

date = {2019-02-06},

journal = {International journal of molecular sciences},

volume = {20},

number = {4},

pages = {E847},

abstract = {The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_112,

title = {Dual inhibition of PI3K/mTOR signaling in chemoresistant AML primary cells.},

author = {Bertacchini J and Frasson C and Chiarini F and D'Avella D and Accordi B and Anselmi L and Barozzi P and Foghieri F and Luppi M and Martelli AM and Basso G and Najmaldin S and Khosravi A and Rahim F and Marmiroli S},

url = {10.1016/j.jbior.2018.03.001},

doi = {10.1016/j.jbior.2018.03.001},

year  = {2018},

date = {2018-02-14},

journal = {Advances in biological regulation},

volume = {68},

number = {2},

pages = {9},

abstract = {A main cause of treatment failure for AML patients is resistance to chemotherapy. Survival of AML cells may depend on mechanisms that elude conventional drugs action and/or on the presence of leukemia initiating cells at diagnosis, and their persistence after therapy. MDR1 gene is an ATP-dependent drug efflux pump known to be a risk factor for the emergence of resistance, when combined to unstable cytogenetic profile of AML patients. In the present study, we analyzed the sensitivity to conventional chemotherapeutic drugs of 26 samples of primary blasts collected from AML patients at diagnosis. Detection of cell viability and apoptosis allowed to identify two group of samples, one resistant and one sensitive to in vitro treatment. The cells were then analyzed for the presence and the activity of P-glycoprotein. A comparative analysis showed that resistant samples exhibited a high level of MDR1 mRNA as well as of P-glycoprotein content and activity. Moreover, they also displayed high PI3K signaling. Therefore, we checked whether the association with signaling inhibitors might resensitize resistant samples to chemo-drugs. The combination showed a very potent cytotoxic effect, possibly through down modulation of MDR1, which was maintained also when primary blasts were co-cultured with human stromal cells. Remarkably, dual PI3K/mTOR inactivation was cytotoxic also to leukemia initiating cells. All together, our findings indicate that signaling activation profiling associated to gene expression can be very useful to stratify patients and improve therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_135,

title = {Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia.},

author = {Evangelisti C and Cappellini A and Oliveira M and Fragoso R and Barata JT and Bertaina A and Locatelli F and Simioni C and Neri LM and Chiarini F and Lonetti A and Buontempo F and Orsini E and Pession A and Manzoli L and Martelli AM and Evangelisti C},

url = {http://onlinelibrary.wiley.com/doi/10.1002/jcp.26135/abstract},

doi = {10.1002/jcp.26135},

year  = {2018},

date = {2018-03-23},

journal = {Journal of cellular physiology},

volume = {233},

number = {3},

pages = {1796-1811},

abstract = {Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stroma-induced DEX-resistance. Finally, gene expression analysis documented that, on one hand the combination consisting of a pan PI3K p110 inhibitor and DEX strengthened the DEX-induced up- or down-regulation of several genes involved in apoptosis, while on the other, it rescued the effects of genes that might be involved in GC-resistance. Overall, our findings strongly suggest that PI3K p110 inhibition could be a promising strategy for treating B-ALL patients by improving GC therapeutic effects and/or overcoming GC-resistance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_121,

title = {Therapeutic targeting of CK2 in acute and chronic leukemias.},

author = {Buontempo F and McCubrey JA and Orsini E and Ruzzene M and Cappellini A and Lonetti A and Evangelisti C and Chiarini F and Evangelisti C and Barata JT and Martelli AM},

url = {https://www.nature.com/articles/leu2017301},

doi = {10.1038/leu.2017.301},

year  = {2018},

date = {2018-01-11},

journal = {Leukemia},

volume = {32},

number = {1},

pages = {1-10},

abstract = {CK2 is a ubiquitously expressed, constitutively active Ser/Thr protein kinase, which is considered the most pleiotropic protein kinase in the human kinome. Such a pleiotropy explains the involvement of CK2 in many cellular events. However, its predominant roles are stimulation of cell growth and prevention of apoptosis. High levels of CK2 messenger RNA and protein are associated with CK2 pathological functions in human cancers. Over the last decade, basic and translational studies have provided evidence of CK2 as a pivotal molecule driving the growth of different blood malignancies. CK2 overexpression has been demonstrated in nearly all the types of hematological cancers, including acute and chronic leukemias, where CK2 is a key regulator of signaling networks critical for cell proliferation, survival and drug resistance. The findings that emerged from these studies suggest that CK2 could be a valuable therapeutic target in leukemias and supported the initiation of clinical trials using CK2 antagonists. In this review, we summarize the recent advances on the understanding of the signaling pathways involved in CK2 inhibition-mediated effects with a particular emphasis on the combinatorial use of CK2 inhibitors as novel therapeutic strategies for treating both acute and chronic leukemia patients.Leukemia advance online publication, 24 October 2017},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_136,

title = {Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update.},

author = {Evangelisti C and Chiarini F and McCubrey JA and Martelli AM},

url = {https://www.mdpi.com/1422-0067/19/7/1878},

doi = {10.3390/ijms19071878},

year  = {2018},

date = {2018-01-26},

journal = {International journal of molecular sciences},

volume = {19},

number = {7},

pages = {pii: E1878},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_197,

title = {Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene.},

author = {Masetti R and Bertuccio SN and Astolfi A and Chiarini F and Lonetti A and Indio V and De Luca M and Bandini J and Serravalle S and Franzoni M and Pigazzi M and Martelli AM and Basso G and Locatelli F and Pession A},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251306/},

doi = {10.1186/s13045-017-0396-0},

year  = {2017},

date = {2017-01-21},

journal = {Journal of hematology & oncology },

volume = {10},

number = {1},

pages = {26},

abstract = {BACKGROUND: CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. METHODS: We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. RESULTS: As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. CONCLUSIONS: Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_320,

title = {Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting.},

author = {Chiarini F and Lonetti A and Evangelisti C and Buontempo F and Orsini E and Evangelisti C and Cappellini A and Neri LM and McCubrey JA and Martelli AM},

url = {http://www.sciencedirect.com/science/article/pii/S0167488915002931},

doi = {10.1016/j.bbamcr.2015.08.015. },

year  = {2016},

date = {2016-02-18},

journal = {Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research},

volume = {1863},

number = {3},

pages = {449-463},

abstract = {The bone marrow (BM) microenvironment regulates the properties of healthy hematopoietic stem cells (HSCs) localized in specific niches. Two distinct microenvironmental niches have been identified in the BM, the "osteoblastic (endosteal)" and "vascular" niches. Nevertheless, these niches provide sanctuaries where subsets of leukemic cells escape chemotherapy-induced death and acquire a drug-resistant phenotype. Moreover, it is emerging that leukemia cells are able to remodel the BM niches into malignant niches which better support neoplastic cell survival and proliferation. This review focuses on the cellular and molecular biology of microenvironment/leukemia interactions in acute lymphoblastic leukemia (ALL) of both B- and T-cell lineage. We shall also highlight the emerging role of exosomes/microvesicles as efficient messengers for cell-to-cell communication in leukemia settings. Studies on the interactions between the BM microenvironment and ALL cells have led to the discovery of potential therapeutic targets which include cytokines/chemokines and their receptors, adhesion molecules, signal transduction pathways, and hypoxia-related proteins. The complex interplays between leukemic cells and BM microenvironment components provide a rationale for innovative, molecularly targeted therapies, designed to improve ALL patient outcome. A better understanding of the contribution of the BM microenvironment to the process of leukemogenesis and leukemia persistence after initial remission, may provide new targets that will allow destruction of leukemia cells without adversely affecting healthy HSCs. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis,Inflammation, and Immune Surveillance. Guest Editors: Peter Ruvolo and Gregg L. Semenza. Copyright 2015 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_294,

title = {Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway.},

author = {Lonetti A and Cappellini A and Bertaina A and Locatelli F and Pession A and Buontempo F and Evangelisti C and Evangelisti C and Orsini E and Zambonin L and Neri LM and Martelli AM and Chiarini F},

url = {https://jhoonline.biomedcentral.com/articles/10.1186/s13045-016-0344-4},

doi = {10.1186/s13045-016-0344-4},

year  = {2016},

date = {2016-10-24},

journal = {Journal Of Hematology & Oncology },

volume = {9},

number = {1},

pages = {114},

abstract = {BACKGROUND: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine. METHODS: The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. RESULTS: Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. CONCLUSIONS: These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_255,

title = {Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB.},

author = {Buontempo F and Orsini E and Lonetti A and Cappellini A and Chiarini F and Evangelisti C and Evangelisti C and Melchionda F and Pession A and Bertaina A and Locatelli F and Bertacchini J and Neri LM and McCubrey JA and Martelli AM},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=6361&pubmed-linkout=1},

doi = {10.18632/oncotarget.6361},

year  = {2016},

date = {2016-01-22},

journal = {Oncotarget},

volume = {7},

number = {2},

pages = {1323-1340},

abstract = {The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_275,

title = {Therapeutic potential of targeting sphingosine kinases and sphingosine 1-phosphate in hematological malignancies.},

author = {Evangelisti C and Evangelisti C and Buontempo F and Lonetti A and Orsini E and Chiarini F and Barata JT and Pyne S and Pyne NJ and Martelli AM},

editor = {Ardizzoni A},

doi = {10.1038/leu.2016.208},

year  = {2016},

date = {2016-11-17},

journal = {Leukemia},

volume = {30},

number = {11},

pages = {2142-2151},

abstract = {Sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P), are bioactive molecules that have important functions in a variety of cellular processes, which include proliferation, survival, differentiation and cellular responses to stress. Sphingolipids have a major impact on determination of the cell fate by contributing to either cell survival or death. While ceramide and sphingosine are usually considered to induce cell death, S1P promotes survival of cells. Sphingosine kinases (SPHKs) are the enzymes that catalyze the conversion of sphingosine to S1P. There are two isoforms, SPHK1 and SPHK2, which are encoded by different genes. SPHK1 has recently been implicated in contributing to cell transformation, tumor angiogenesis, and metastatic spread, as well as cancer cell multidrug-resistance. More recent findings suggest that SPHK2 also has a role in cancer progression. This review is an overview of our understanding of the role of SPHKs and S1P in hematopoietic malignancies and provides information on the current status of SPHK inhibitors with respect to their therapeutic potential in the treatment of hematological cancers.Leukemia accepted article preview online, 27 July 2016. doi:10.1038/leu.2016.208.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_339,

title = {Autophagy in acute leukemias: A double-edged sword with important therapeutic implications},

author = {Evangelisti C and Evangelisti C and Chiarini F and Lonetti A and Buontempo F and Neri LM and McCubrey JA and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488914003486?via%3Dihub},

doi = {10.1016/j.bbamcr.2014.09.023},

year  = {2015},

date = {2015-02-18},

journal = {Biochimica et Biophysica Acta (BBA) - Molecular Cell Research},

volume = {1853},

number = {1},

pages = {14-26},

abstract = {Macroautophagy, usually referred to as autophagy, is a degradative pathway wherein cytoplasmatic components such as aggregated/misfolded proteins and organelles are engulfed within double-membrane vesicles (autophagosomes) and then delivered to lysosomes for degradation. Autophagy plays an important role in the regulation of numerous physiological functions, including hematopoiesis, through elimination of aggregated/misfolded proteins, and damaged/superfluous organelles. The catabolic products of autophagy (amino acids, fatty acids, nucleotides) are released into the cytosol from autophagolysosomes and recycled into bio-energetic pathways. Therefore, autophagy allows cells to survive starvation and other unfavorable conditions, including hypoxia, heat shock, and microbial pathogens. Nevertheless, depending upon the cell context and functional status, autophagy can also serve as a death mechanism. The cohort of proteins that constitute the autophagy machinery function in a complex, multistep biochemical pathway which has been partially identified over the past decade. Dysregulation of autophagy may contribute to the development of several disorders, including acute leukemias. In this kind of hematologic malignancies, autophagy can either act as a chemo-resistance mechanism or have tumor suppressive functions, depending on the context. Therefore, strategies exploiting autophagy, either for activating or inhibiting it, could find a broad application for innovative treatment of acute leukemias and could significantly contribute to improved clinical outcomes. These aspects are discussed here after a brief introduction to the autophagic molecular machinery and its roles in hematopoiesis.Copyright  2014 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_351,

title = {Current treatment strategies for inhibiting mTOR in cancer},

author = {Chiarini F and Evangelisti C and McCubrey JA and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0165614714001953?via%3Dihub},

doi = {10.1016/j.tips.2014.11.004},

year  = {2015},

date = {2015-02-11},

journal = {Trends in Pharmacological Sciences},

volume = {36},

number = {2},

abstract = {Mammalian target of rapamycin (mTOR) is a Ser/Thr kinase that regulates a wide range of functions, including cell growth, proliferation, survival, autophagy, metabolism, and cytoskeletal organization. mTOR activity is dysregulated in several human disorders, including cancer. The crucial role of mTOR in cancer cell biology has stimulated interest in mTOR inhibitors, placing mTOR on the radar of the pharmaceutical industry. Several mTOR inhibitors have already undergone clinical trials for treating tumors, without great success, although mTOR inhibitors are approved for the treatment of some types of cancer, including advanced renal cell carcinoma. However, the role of mTOR inhibitors in cancer treatment continues to evolve as new compounds are continuously being disclosed. Here we review the three classes of mTOR inhibitors currently available for treating cancer patients. Moreover, we highlight efforts to identify markers of resistance and sensitivity to mTOR inhibition that could prove useful in the emerging field of personalized medicine.Copyright 2014 Elsevier Ltd. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_393,

title = {PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors.},

author = {Lonetti A and Cappellini A and Spartà AM and Chiarini F and Buontempo F and Evangelisti C and Evangelisti C and Orsini E and McCubrey JA and Martelli AM},

url = {https://www.fasebj.org/doi/full/10.1096/fj.14-259051?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&},

year  = {2015},

date = {2015-04-15},

journal = {Oncotarget},

volume = {6},

number = {12},

pages = {10399-10414},

abstract = {Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110γ/δ inhibition. Intriguingly, the dual p110γ/δ inhibitor IPI-145 was effective in Loucy cells, which are representative of early T-precursor (ETP)-ALL, a T-ALL subtype associated with a poor outcome. PTEN gene deletion did not confer a peculiar reliance of T-ALL cells on PI3K activity for their proliferation/survival, as PTEN was inactivated in PTEN non deleted cells, due to posttranslational mechanisms. PI3K pan-inhibition suppressed Akt activation and induced caspase-independent apoptosis. We further demonstrated that in some T-ALL cell lines, autophagy could exert a protective role against PI3K inhibition. Our findings strongly support clinical application of class I PI3K pan-inhibitors in T-ALL treatment, with the possible exception of ETP-ALL cases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_394,

title = {PLCβ1a and PLCβ1b selective regulation and cyclin D3 modulation reduced by kinamycin F during k562 cell differentiation.},

author = {Bavelloni A and Dmitrienko GI and Goodfellow VJ and Ghavami A and Piazzi M and Blalock WL and Chiarini F and Cocco L and Faenza I},

url = {https://onlinelibrary.wiley.com/doi/full/10.1002/jcp.24776},

doi = {10.1002/jcp.24776},

year  = {2015},

date = {2015-03-03},

journal = {Journal of Cellular Physiology},

volume = {230},

number = {3},

abstract = {Here we report that both PLCβ1a and PLCβ1b are relevant regulators of erythropoiesis in that kinamycin F, a potent inducer of γ-globin production in K562 cells, caused a selectively reduction of both PLCβ1 isozymes even though the results point out that the effect of the drug is mainly directed toward the expression of the PLCβ1a isoform. We have identified a different role for the two isozymes as regulators of K562 differentiation process induced by kinamycin F. The overexpression of PLCβ1b induced an increase in γ-globin expression even in the absence of kinamycin F. Moreover during K562 differentiation, cyclin D3 level is regulated by PLCβ1 signaling pathway. Namely the amplification of the expression of the PLCβ1a, but not of PLCβ1b, is able to maintain high levels of expression of cyclin D3 even after treatment with kinamycin F. This could be due to their different distribution in the cell compartments since the amount of PLCβ1b is mainly present in the nucleus in respect to PLCβ1a. Our data indicate that the amplification of PLCβ1a expression, following treatment with kinamycin F, confers a real advantage to K562 cells viability and protects cells themselves from apoptosis.2014 Wiley Periodicals, Inc., A Wiley Company.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}