ABSTRACT
Background: Aloperine can exert antitumor effects in colorectal cancer; however, it remains obscure whether aloperine can reverse the cisplatin resistance in colorectal cancer (CRC). Objective: To explore the roles of aloperine in the chemosensitivity of the DDP-resistant colorectal cancer cell line HT-29 (HT-29/DDP) and the related mechanism. Results: Aloperine can inhibit the proliferation of both HT-29 and HT-29/DDP cells in a dose-dependent manner; moreover, aloperine can significantly increase the sensitivity of HT-29/DDP cells to DDP; finally, HIF-1α and p-ERK was upregulated in HT-29/DDP cells and transient over-expression of HIF-1α has blocked aloperine+DDP induced anti-proliferative and pro-apoptotic effects on HT-29/DDP cells. Conclusion: We are reporting for the first time that aloperine can increase the sensitivity of HT-29/DDP cells to DDP and reverse cisplatin resistance via downregulating the HIF-1α /ERK signaling pathway.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Colorectal Neoplasms/drug therapy , Piperidines/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HT29 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , MAP Kinase Signaling System/drug effects , Quinolizidines , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVDs). We aimed to investigate the joint effect of homocysteine metabolism gene polymorphisms, as well as the folate deficiency on the risk of HHcy in a Chinese hypertensive population. METHODS: This study enrolled 480 hypertensive patients aged 28 - 75 from six hospitals in different Chinese regions from 9/2005 - 12/2005. Known genotypes of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G were detected by PCRRFLP methods. Serum Hcy was measured by high-performance liquid chromatography and serum folate was measured by chemiluminescent immunoassay. RESULTS: MTHFR C677T and MTR A2756G can independently elevate the risk of HHcy (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA, p = 0.026, respectively), whereas MTHFR A1298C decreased HHcy risk (AC + CC vs. AA, p < 0.001) and showed a protective effect against HHcy risk. Importantly, the joint effect of these risk genotypes showed significantly higher odds of HHcy than non-risk genotypes, especially the patients with four risk genotypes. It is noteworthy that this deleterious effect was aggravated by folate deficiency. These findings were verified by generalized multifactor dimensionality reduction model (p = 0.001) and a cumulative effects model (p < 0.001). CONCLUSIONS: We have first demonstrated that the joint effect of homocysteine metabolism gene polymorphisms and folate deficiency lead to dramatic elevations in the HHcy risk.
