79 research outputs found
Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab
The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients
Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy
The goal of cancer pharmacogenomics is to obtain benefit from personalized approaches of cancer treatment and prevention. Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and targets, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. Although a considerable amount of new targeted agents have been designed based on a finely understanding of molecular alterations in cancer, a wide gap between pharmacogenomic knowledge and clinical application still persists. This review focuses on the relevance of mutational analyses in predicting individual response to antitumor therapy, in order to improve the translational impact of genetic information on clinical practice
PTHrP produced by myeloma plasma cells regulates their survival and pro-osteoclast activity for bone disease progression.
To promote their survival and progression in the skeleton, osteotropic malignancies of breast, lung, and prostate produce parathyroid
hormoneârelated protein (PTHrP), which induces hypercalcemia. PTHrP serum elevations have also been described in multiple
myeloma (MM), although their role is not well defined. When we investigated MM cells from patients and cell lines, we found that
PTHrP and its receptor (PTHâR1) are highly expressed, and that PTHrP is secreted both as a fullâlength molecule and as small subunits.
Among these subunits, the midâregion, including the nuclear localization sequence (NLS), exerted a proliferative effect because it was
accumulated in nuclei of MM cells surviving in starvation conditions. This was confirmed by increased transcription of several genes
enrolled in proliferation and apoptosis control. PTHrP was also found to stimulate PTHâR1 inMMcells. PTHâR1âs selective activation by
the fullâlength PTHrP molecule or the NH2âterminal fragment resulted in a significant increase of intracellular Ca2ĂŸ influx, cyclic
adenosine monophosphate (cAMP) content, and expression of receptor activator of NFâkB ligand (RANKL) and monocyte
chemoattractant proteinâ1 (MCPâ1). Our data definitely clarify the role of PTHrP in MM. The PTHrP peptide is functionally secreted by
malignant plasma cells and contributes to MM tumor biology and progression, both by intracrine maintenance of cell proliferation in
stress conditions and by autocrine or paracrine stimulation of PTHâR1, which in turn reinforces the production of osteoclastogenic
factors
An imbalance between Beclin-1 and p62 expression promotes the proliferation of myeloma cells through autophagy regulation.
Autophagy occurs in tumor cells acquiring cytotoxic drug resistance and its activation may impair their susceptibility to apoptosis in response to apoptogen agents. We investigated the pro-apoptotic effect of dexamethasone (Dex) on MM cell lines (U266, INA-6, LR5-8226, LIG, and MCC2) and primary malignant plasma cells from naĂŻve and refractory/relapsed patients. We evaluated the transcriptional and ultrastructural events leading to autophagy by measuring Beclin-1 and p62 levels and transmission electronic microscopy. Autophagy was inhibited by hydroxychloroquine (HCQ), whereas the ability of Dex-resistant MM cells to recover the susceptibility to apoptosis was measured. A direct relationship between autophagy and Beclin-1 or LC3/Atg8 levels was observed, whereas their mRNAs were inversely correlated to p62 expression. Starvation strongly activated autophagy by inducing cellular, transcriptional, and ultrastructural modifications that were reversed by HCQ. Taken together, these data suggest that autophagy is a potential mechanism leading to drug resistance in MM, and suggest Beclin-1 and p62 as early markers of cell susceptibility to apoptosis. The combination of HCQ with novel agents may thus be considered to improve the therapeutic response in relapsed/resistant MM patients
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