Rumex Vesicarius L. extract improves the efficacy of doxorubicin in triple-negative breast cancer through inhibiting Bcl2, mTOR, JNK1 and augmenting p21 expression

Abstract

Doxorubicin (DOX) is a potent chemotherapeutic drug; however, its use is limited because it induces dose-dependent oxidative stress causing severe adverse effects. Rumex Vesicarius L. (RMX) is a plant used in traditional medicine for its multiple therapeutic virtues including antioxidant potential. We aimed to determine the potency of RMX alone and in combination with DOX against the invasive triple-negative breast cancer (TNBC) cell line MDA-MB-231, and to deduce the underlying mechanism of action by in vitro and in silico analyses. We found that the RMX extract alone and in combination with DOX significantly inhibited the cancer cell proliferation with a 50% inhibitory concentration (IC50) of 2.12 and 0.5 μM respectively. Furthermore, combined treatment of RMX and DOX has induced significant reductions in the relative gene expression of the survival/anti-apoptosis and invasion genes mTOR, Bcl-2, and JNK respectively, while the expression of the p21 tumor suppressor gene was increased. In silico analysis of the RMX extract indicated that some of its bioactive compounds exhibit superior affinity to inhibit the oncogene p21-activated kinase 4 (PAK4), which functions as an inhibitor of the p21 gene. In conclusion, this study reveals that the RMX extract enhances the anticancer efficacy of DOX through molecular mechanisms involving downregulation of mTOR, Bcl-2, and JNK1, while augmenting p21 expression in TNBC possibly by targeting PAK4 as indicated through in vitro and in silico analyses. Finally, we recommend RMX and its bioactive compounds for further in vivo studies to confirm their potential in cancer therapy.