Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metformin, a drug from the biguanide class, is now one of the most widely used drugs in the treatment of type 2 diabetes. This drug was also used in the treatment of polycystic ovarian syndrome and recent reports indicate the possibility of using this drug in oncology. Latest findings show that metformin has an anticancer effect. Influencing the transduction mechanisms primarily through activation of protein kinase activated by 5'AMP (AMPK) regulates the activity of the AMPK/mTOR signaling pathway. MTOR pathway dysregulation may be a factor in the pathogenesis of various human diseases, especially cancers. Overactivation of mTOR is observed in malignant cells and is associated with their resistance to treatment. It can therefore be concluded that metformin as an inhibitor of mTOR may be a factor that suppresses tumor development. There are also studies showing that metformin prevents the formation of metastases, reducing tumor vasculature and improves the effectiveness of anticancer drugs. The anticancer effect of metformin has been proven in the treatment of colorectal and breast cancer. The current studies reports the positive effects in the treatment of gynecological cancers such as ovarian, endometrial and cervical cancer. Incidence for these tumors in 2009 in Poland was: for ovarian cancer 11.01100000; for endometrial cancer 15.0/100000; for cervical cancer 10.5/100000. Metformin has antitumor activity in monotherapy and also synergistically with other anticancer agents. Metformin has antiproliferative properties; reduces the VEGF levels, causing a reduction in tumor vasculature; causes an increase in progesterone receptor, which increases the response to hormonal therapy; inhibits the expression of glyoxalase I, mediating resistance to chemotherapy; decreases in the concentration of human telomerase; reduces the activity of Akt and Erk kinases, key regulators of metabolism and progression of tumors and also inhibits the formation of metastases.
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PMID:[Metformin--new treatment strategies for gynecologic neoplasms]. 2387 9

We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201.
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PMID:ONC201 kills breast cancer cells in vitro by targeting mitochondria. 2971 18


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