Rg3 can induce apoptosis and cell cycle arrest in different cancer cells via different pathways such as downregulating hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) [18], [19], [20] and [21]. Rk1 was investigated to inhibit telomerase activity and cell growth and induce apoptosis through activation of caspase-8 and -3 via ERK pathway, whereas another article demonstrated that Rk1 could induce G1 arrest and autophagy [22] and [23]. Rg5 blocks the cell cycle at the Gl/S transition phase by increasing p21Cip/WAF1 and decreasing cyclin E and CDK2 [24]. Epirubicin is a third-generation anthracycline that treats a broad
spectrum of cancers, including cervical, breast, lung (especially small cell lung
cancer), ovarian, stomach, see more colon, and bladder, and malignant lymphoma [25] and [26]. Similar to widely used Ruxolitinib anticancer drugs, epirubicin exhibits some adverse effects on blood, the stomach, and the heart; these effects largely depend on the applied doses [27]. Paclitaxel is another important anticancer drug that is widely used as a chemotherapeutic agent for treating ovarian, breast, lung, colorectal, bladder, prostate, and gastric cancer, melanoma, and lymphoma [28], [29] and [30]. Paclitaxel, which is an inhibitor of microtubule degradation, induces cell cycle arrest at the G2/M phase [31] and [32] and ultimately apoptosis [33] and [34]. This drug also has significant adverse effects, such as hypersensitivity, neutropenia syndrome, neurotoxicity, heart rhythm
disorders, and intracellular toxicity [35], [36] and [37]. Therefore, developing adjuvant agents to potentiate the anticancer activities of epirubicin and paclitaxel and to minimize their adverse effects is significant. In the current study, SG significantly Avelestat (AZD9668) potentiated the anticancer activities of epirubicin and paclitaxel in a synergistic manner. These effects were associated with the increased mitochondrial accumulation of both Bax and Bak that led to an enhanced cytochrome c release, caspase-9/-3 activation, and apoptosis. SG was provided by Dr. Jeong Hill Park, College of Pharmacy, Seoul National University, Seoul, Korea. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), and dimethylsulfoxide (DMSO) were purchased from Sigma–Aldrich (St. Louis, MO, USA). Epirubicin was acquired from Pfizer (Wuxi, China). Newborn calf serum and Dulbecco modified Eagle’s medium (DMEM) were purchased from Gibco (Life Technologies, Grand Island, NY, USA). Caspase substrates Ac-DEVD-AFC, Ac-IETD-AFC, and Ac-LEHD-AFC were purchased from Calbiochem (La Jolla, CA, USA). The Mitochondria Isolation Kit was purchased from Pierce (Rockford, IL, USA). Annexin V-FITC Apoptosis Detection Kit was purchased from KeyGEN Biotech (Nanjing, China).