Chemoresistance in multidrug-resistant (MDR) cells over expressing P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major obstacle to successful chemotherapy for colorectal cancer. Previous studies have indicated that sinomenine can enhance the absorption of various P-gp substrates. In the present study, we investigated the effect of sinomenine on the chemoresistance in colon cancer cells and explored the underlying mechanism. We developed multidrug-resistant Caco-2 (MDR-Caco-2) cells by exposure of Caco-2 cells to increasing concentrations of doxorubicin. We identified overexpression of COX-2 and MDR-1 genes as well as activation of the NF-κB signal pathway in MDR-Caco-2 cells. Importantly, we found that sinomenine enhances the sensitivity of MDR-Caco-2 cells towards doxorubicin by downregulating MDR-1 and COX-2 expression through inhibition of the NF-κB signaling pathway. These findings provide a new potential strategy for the reversal of P-gp-mediated anticancer drug resistance.
The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, which has affected the early diagnosis and treatment of HCC and the survival time of patients. MicroRNAs (miRNAs) are a class of evolutionarily conserved small, non-coding RNAs, which regulate the expression of various genes post-transcriptionally. Emerging evidence indicates that the key enzymes involved in the miRNA biosynthesis pathway and some tumor-specific miRNAs are widely deregulated or upregulated in HCC and closely associated with the occurrence and development of various cancers, including HCC. Early studies have shown that miRNAs have critical roles in HCC progression by targeting many critical protein-coding genes, thereby contributing to the promotion of cell proliferation; the avoidance of apoptosis, inducing via angiogenesis; and the activation of invasion and metastasis pathways. Experimental data indicate that discovery of increasing numbers of aberrantly expressed miRNAs has opened up a new field for investigating the molecular mechanism of HCC progression. In this review, we describe the current knowledge about the roles and validated targets of miRNAs in the above pathways that are known to be hallmarks of HCC, and we also describe the influence of genetic variations in miRNA biosynthesis and genes.
The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, which has affected the early diagnosis and treatment of HCC and the survival time of patients. MicroRNAs (miRNAs) are a class of evolutionarily conserved small, non-coding RNAs, which regulate the expression of various genes post-transcriptionally. Emerging evidence indicates that the key enzymes involved in the miRNA biosynthesis pathway and some tumor-specific miRNAs are widely deregulated or upregulated in HCC and closely associated with the occurrence and development of various cancers, including HCC. Early studies have shown that miRNAs have critical roles in HCC progression by targeting many critical protein-coding genes, thereby contributing to the promotion of cell proliferation; the avoidance of apoptosis, inducing via angiogenesis; and the activation of invasion and metastasis pathways. Experimental data indicate that discovery of increasing numbers of aberrantly expressed miRNAs has opened up a new field for investigating the molecular mechanism of HCC progression. In this review, we describe the current knowledge about the roles and validated targets of miRNAs in the above pathways that are known to be hallmarks of HCC, and we also describe the influence of genetic variations in miRNA biosynthesis and genes.
Background: Clear cell renal cell carcinoma (ccRCC) frequently involves the inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Loss of VHL functions lead to the accumulation of hypoxia-inducible factors (HIFs). HIF2α has been regarded as a key tumorigenic driver of ccRCC and an attractive therapeutic target. Arrowhead has developed a RNA interference therapeutic (HIF2 RNAi) to selectively target and silence HIF2α expression, using a proprietary targeted-RNAi molecule (TRiM™) delivery platform for the treatment of ccRCC. The TRiM™ based Hif2 construct comprises a highly potent RNAi trigger using stabilization chemistries, targeting ligands to facilitate delivery, and structures to enhance pharmacokinetics (PK). The optimization of HIF2 RNAi to enhance the potency and safety profile to maximize the potential clinical success is described. Methods: Functional optimization of HIF2 RNAi was evaluated in an orthotopic ccRCC tumor xenograft model established with A498 ccRCC cells that stably expresses the reporter gene SEAP (secreted embryonic alkaline phosphatase) as a serum biomarker for monitoring tumor growth. HIF2 RNAi was delivered by intravenous injections. HIF2α gene silencing was evaluated by isolating tumor RNA and measuring relative gene expression by qRT-PCR. Results: We demonstrate that to achieve deep HIF2α mRNA knockdown (KD), functionalizing HIF2 RNAi with PK enhancement and tumor targeting ligand (TTL) is required. Optimization of the HIF2 RNAi construct enabled a 10-fold improvement in potency. Evaluation of a loading dose regimen improved overall HIF2α mRNA KD compared to a single administration of equal total dosage. Utilizing this strategy, we demonstrated that silencing of HIF2α mRNA (85% KD) resulted in tumor growth inhibition in the A498 xenograft model. Significant improvement in overall survival was also seen in a patient derived xenograft model. Histology evaluation of tumor samples revealed extensive tumor destruction with clusters of apoptotic cells and necrosis. Follow-up studies suggest that loading doses can be administered four hours apart without loss in potency. This allows dosing to be completed in one day and may be more acceptable in clinical settings. The maximum HIF2α mRNA KD after a single dose of HIF2 RNAi was achieved about 7 days after dosing and sustained for about one week in the xenograft model. This suggests that dosing can likely be less frequent in clinical settings. An exploratory toxicity study in rats predicts a wide safety margin. Conclusions: We demonstrate that the TRiM™ delivery platform can be utilized to deliver a RNAi therapeutic selectively targeting HIF2α for the treatment of ccRCC. This represents a novel therapeutic approach either as a monotherapy or in combination with other therapies in seeking better tolerated and/or more effective treatment for ccRCC. Citation Format: So C. Wong, Anthony Nicholas, Jeff Carlson, Dongxu Shu, Che Liu, Rui Chu, Amanda Frankiewicz, Holly Hamilton, Casi Schienebeck, Aaron Andersen, Matthew Fowler-Watters, Stephanie Bertin, Xiaokai Li, Bo Chen, Josh Schumacher, Julia Hegge, Bruce Given, Zhen Li. Optimizing the potency and dosing design for ARO-HIF2: An RNAi therapeutic for clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4775.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.