Multi-drug resistance reversal effect of tenacissoside I through impeding EGFR methylation mediated by PRMT1 inhibition

Cancer multidrug resistance (MDR) hampers the treatment outcome of various chemotherapeutics. Novel strategies, including developing MDR reversal agent, are urgently necessary to improve this scenario. Here, we demonstrated that tenacissoside I (TI), a compound obtained from Marsdenia tenacissima (Roxb.) Wight et Arn, which is widely used in clinical practice as a traditional ethnic medicine to treat various cancers, exerts a significant MDR reversal effect, specifically in ABCB1-mediated MDR, in cancer cells. TI reversed SW620/AD300 and KBV200 cells resistance to doxorubicin and paclitaxel through either downregulating ABCB1 expression or reducing ABCB1 drug transport function. Mechanistically, PRMT1, whose expression represents poor prognosis and was positively correlated with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI treated SW620/AD300 cells. SW620/AD300 and KBV200 cells display a higher level of EGFR asymmetric dimethylarginine (aDMA) and a stronger interaction of PRMT1 and EGFR than their parental cells. Additionally, downregulated PRMT1 by TI crippled PRMT1-mediated aDMA of EGFR, the interaction between PRMT1 and EGFR, as well as EGFR downstream signaling in SW620/AD300 and KBV200 cells. However, these effects of TI were remarkably reversed by PRMT1 over-expression. Furthermore, TI reversed resistance to paclitaxel in xenograft models with undetectable toxicities. Our study demonstrates TI’s MDR reversal effect, specifically in ABCB1-mediated MDR human cancer cells, mechanistically involved with an impairment of PRMT1-mediated aDMA of EGFR through PRMT1 inhibition. Our findings provide significant bases for the potentiality of TI as an MDR modulator in improving the clinical outcome of chemotherapy.