Synergistic antitumor effect of ginsenoside Rg3 and cisplatin in cisplatin-resistant bladder tumor cell line

Abstract

Abstract. Cisplatin-based chemotherapy is the first-line treatment for metastatic urothelial cell carcinoma. However, for cisplatin-resistant cases, no chemotherapeutic agent has been established as a standard of treatment. This study aimed to investigate the synergistic antitumor effect of ginsenoside Rg3 on cisplatin in cisplatin-resistant bladder cancer cells (T24R2). T24R2 cells were treated with cisplatin and/or ginsenoside Rg3. Cell viability was assessed by the Cell Counting Kit-8 and clonogenic assays. Synergism between ginsenoside Rg3 and cisplatin was determined when the combination index was <1.0. Flow cytometry was used to evaluate the cell cycle distribution. To estimate the changes of proteins associated with the cell cycle and apoptosis following the treatment of ginsenoside Rg3, western blotting and densitometric assays were performed for caspase-3, -8 and -9, cyclin B1, Bcl-2, Bad, p21 and cytochrome c. The Cell Counting Kit-8 and clonogenic assays showed the synergistic antitumor effect of ginsenoside Rg3 on cisplatin, while the combination index was <1.0, confirming the synergism. Cell cycle alterations at the G2/M phase caused by cisplatin were greater after the combination with ginsenoside Rg3. Western blotting and densitometric assay showed that the expression of Bcl-2 was decreased after the combined treatment of ginsenoside Rg3 and cisplatin, whereas the expression of cytochrome c and caspase-3 were increased, suggesting the activation of the intrinsic apoptotic pathway. In conclusion, ginsenoside Rg3 inhibited the proliferation of cisplatin-resistant bladder cancer cells in a synergistic manner with cisplatin. Activation of the intrinsic apoptotic pathway and the enhancement of cell cycle alterations are possible explanations for this result.

Clinical benefit from EGFR-TKI plus ginsenoside Rg3 in patients with advanced non-small cell lung cancer harboring EGFR active mutation

“…Preclinical studies have indicated that ginsenoside Rg3 is able to exert anticancer effects by inhibiting angiogenesis and tumor growth in many solid tumors such as hepatocellular carcinoma [18], bladder cancer [19], breast cancer [20], ovarian cancer [21] and colorectal cancer [22]. A previous study has also shown the inhibitory effect of ginsenoside Rg3 combined with gemcitabine on the growth of lung cancer in mice [23].…”

Saponins as chemosensitizing substances that improve effectiveness and selectivity of anticancer drug—Minireview of in vitro studies

“…Most research papers cited in this review were focused solely on the mechanisms of action and the efficiency of combined saponin/drug use, and these concerned mainly dammarane‐type saponins such as ginsenosides isolated from Panax sp. (Lee et al, ; Park et al, ; Wang et al, ; Yang et al, ; Zhang et al, ; Zhang et al, ; Zhang & Li, ). However, it is not possible to draw any conclusions concerning the potential SAR.…”

“…Tubeimoside I, isolated from the tubers of Bolbostemma paniculatum (Cucurbitaceae), exerts an antiproliferative effect and sensitizes human ovarian cancer A2780/DDP cells to S. M. Kim et al (2009Kim et al ( , 2010 cisplatin by inducing apoptosis, down-regulating ERK1/2, and upregulating p38 signaling pathways . Likewise, ginsenoside Rg 3 inhibits the proliferation of cisplatin-resistant bladder cancer cells (T24R2) in a synergistic manner with cisplatin (Lee et al, 2014). Combined treatment (cisplatin and ginsenoside Rg3) activates the intrinsic apoptotic pathway and enhances cell cycle alteration.…”

“…Most research papers cited in this review were focused solely on the mechanisms of action and the efficiency of combined saponin/drug use, and these concerned mainly dammarane-type saponins such as ginsenosides isolated from Panax sp. (Lee et al, 2014;Park et al, 2015;Wang et al, 2015;Yang et al, 2012;Zhang et al, 2008;Zhang et al, 2009;Zhang & Li, 2016 enhanced the effect of therapy and/or reduced toxicity. It is also interesting that in most saponins one of the sugar chains is attached through an ester linkage at C-28.…”

Understanding Thai consumer attitudes and expectations of ginseng food products

“…It is widely used as a traditional medicine because of its health benefits. Several studies have demonstrated the beneficial effects of ginseng, such as blood circulation improvement, blood cholesterol improvement, anti‐diabetic (Kang, Lee, Ahn, & Lee, ; Qi, Wang, & Yuan, ; Yuan, Kim, Kim, & Chung, ), neuroprotective activity, memory improvement, anti‐inflammatory (González‐Burgos, Fernandez‐Moriano, & Gómez‐Serranillos, ), anticancer activity (Ahuje, Kim, Kim, Yi, & Cho, ; Lee et al, ; Xu et al, ), anti‐fatigue, anti‐stress effects, immune function improvement (So, Lee, Kim, Hyun, & Han, ; Wang et al, ), and anti‐aging effects (Bjorklund et al, ). Moreover, ginseng is also known to increase vitality, health, and longevity, especially in elderly people (Yang, Ren, Zhang, & Wu, ).…”