Abstract
Multidrug resistance is a significant clinical crisis in cancer treatment and has been linked to the cellular expression of multidrug efflux transporters. The aim of this study was to examine the effects and mechanisms of the metformin derivative HL156A on human multidrug resistance (MDR) cancer cells. Here, HL156A significantly suppressed cell growth and colony formation through G2/M phase cell cycle arrest in MDR cancer cells. HL156A also reduced the wound closure rate and cell migration and induced caspase-3-dependent apoptosis. We found that HL156A inhibited the expression of MDR1 by inhibiting the HOXC6-mediated ERK1/2 signaling pathway and increased the sensitivity to paclitaxel or doxorubicin in MDR cells. Furthermore, HL156A significantly inhibited angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These results suggest the potential of the metformin derivative HL156A as a candidate therapeutic modality for the treatment of human multidrug-resistant cancers.
Highlights
Chemotherapy treatment is often associated with multidrug resistance (MDR), resulting in unsatisfactory treatment outcomes such as intractable tumors or cancer recurrence [1,2]
Recent studies have shown that PI3K-AKTsignaling and Wnt/β-catenin signaling promote the expression of MDR-1 mRNA by inducing the transcription of the MDR-1 gene, while the activation of the MAPK/p38, ERK and JNK/c-Jun/AP-1 pathways regulates MDR-1 expression through both transcriptional and posttranscriptional modifications [13,14]
After treatment with 40 μM HL156A, FaDu/PTX and MCF7/ADR cell proliferation was decreased by 72.8% and 67% at 48 h compared to the control, respectively
Summary
Chemotherapy treatment is often associated with multidrug resistance (MDR), resulting in unsatisfactory treatment outcomes such as intractable tumors or cancer recurrence [1,2]. Several studies have proposed cellular mechanisms of MDR, including increased efflux, reduced influx, activation of coordinately regulated detoxifying systems, DNA repair activation and defective apoptotic pathways [3,4,5,6,7]. Among the ABC transporters, P-glycoprotein (P-gp or ABCB1) is a 170 kDa membrane protein encoded by the MDR-1 gene that has broad cross-resistance specificity for anticancer drugs, including doxorubicin, cisplatin, and Taxol (paclitaxel) [2,3,8]. P-gp prevents the sufficient accumulation of intracellular anticancer drugs by ATP-dependent efflux and helps cancer cells avoid cytotoxic or apoptotic effects [8,9,10]. Recent studies have shown that PI3K-AKTsignaling and Wnt/β-catenin signaling promote the expression of MDR-1 mRNA by inducing the transcription of the MDR-1 gene, while the activation of the MAPK/p38, ERK and JNK/c-Jun/AP-1 pathways regulates MDR-1 expression through both transcriptional and posttranscriptional modifications [13,14]
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