Abstract
Betulinic acid (BA) and its derivatives are a class of high-profile drug candidates, but their anticancer effects on resistant cancer have rarely been reported. Although a few studies indicated mitophagy is related with drug resistance, its role in different cancer types and anticancer agents treatment remains largely unclear. Here, we find that B5G1, a new derivative of BA, induces cell death in multidrug resistant cancer cells HepG2/ADM and MCF-7/ADR through mitochondrial-apoptosis pathway. B5G1 also triggers mitophagy independent on Atg5/Beclin 1. Further mechanistic study indicates that B5G1 upregulates PTEN-induced putative kinase 1 (PINK1) to recruit Parkin to mitochondria followed by ubiquitination of Mfn2 to initiate mitophagy. Inhibition of mitophagy by PINK1 siRNA, mdivi-1, or bafilomycin A1 (Baf A1) promotes B5G1-induced cell death. In addition, ROS production and mitochondrial damage in B5G1-treated HepG2/ADM cells cause mitochondrial apoptosis and mitophagy. In vivo study shown that B5G1 dramatically inhibits HepG2/ADM xenograft growth accompanied by apoptosis and mitophagy induction. Together, our results provide the first demonstration that B5G1, as a novel mitophagy inducer, has the potential to be developed into a drug candidate for treating multidrug resistant cancer.
Highlights
Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters is the primary obstacle to successful cancer chemotherapy[1]
As mitophagy acts as “a double-edged sword” in cancer, we investigated the interaction of B5G1-induced mitophagy and apoptosis in drug-resistant cancer cells using PINK1 Small interfering RNA (siRNA), a mitophagy inhibitor, mdivi-1, and a lysosome inhibitor, bafilomycin A1 (Baf A1)
We report for the first time that B5G1, a derivative of Betulinic acid (BA), overcame multidrug-resistant cancer by inducing mitochondrial apoptosis and mitophagy
Summary
Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters is the primary obstacle to successful cancer chemotherapy[1]. Numerous MDR reversal agents targeting ABC transporters have been developed, poor efficacy and severe side effects have caused their failure in clinical trials[2,3]. The need to explore novel chemotherapeutic agents and effective strategies against resistant cancers is urgent. Several reports suggested that mitophagy contribute to chemotherapeutic efficacy or drug resistance in cancer. Inhibition of the mitochondrial respiratory chain by BAY 87-2243 induced mitophagy-dependent necroptosis and ferroptosis[4]. Targeting orphan nuclear receptor TR3 with a small molecule led to permeability transition pore opening, which results in excessive mitophagy and irreversible A375 cell death[5]. Doxorubicin (Dox)-induced mitophagy contributes to drug resistance in HCT8 human colorectal cancer stem cells.
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