A formulated red ginseng extract inhibits autophagic flux and sensitizes to doxorubicin-induced cell death

Abstract

BackgroundGinseng is believed to have antitumor activity. Autophagy is largely a prosurvival cellular process that is activated in response to cellular stressors, including cytotoxic chemotherapy; therefore, agents that inhibit autophagy can be used as chemosensitizers in cancer treatment. We examined the ability of Korean Red Ginseng extract (RGE) to prevent autophagic flux and to make hepatocellular carcinoma (HCC) cells become more sensitive to doxorubicin.MethodsThe cytotoxic effects of total RGE or its saponin fraction (RGS) on HCC cells were examined by the lactate dehydrogenase assay in a dose- or time-dependent manner. The effect of RGE or RGS on autophagy was measured by analyzing microtubule-associated protein 1A/1B-light chain (LC)3-II expression and LC3 puncta formation in HCC cells. Late-stage autophagy suppression was tested using tandem-labeled green fluorescent protein (GFP)–monomeric red fluorescent protein (mRFP)–LC3.ResultsRGE markedly increased the amount of LC3-II, but green and red puncta in tandem-labeled GFP–mRFP–LC3 remained colocalized over time, indicating that RGE inhibited autophagy at a late stage. Suppression of autophagy through knockdown of key ATG genes increased doxorubicin-induced cell death, suggesting that autophagy induced by doxorubicin has a protective function in HCC. Finally, RGE and RGS markedly sensitized HCC cells, (but not normal liver cells), to doxorubicin-induced cell death.ConclusionOur data suggest that inhibition of late-stage autophagic flux by RGE is important for its potentiation of doxorubicin-induced cancer cell death. Therapy combining RGE with doxorubicin could serve as an effective strategy in the treatment of HCC.

The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets

“…The inhibition of autophagy (with 3MA or ATG5/Beclin1 knockdown) results in the enhancement of apoptotic cell death induced by a number of agents, including physicon [177], fangchinoline [178], Bcl-2 inhibitor ABT-737 (which induces autophagy via JNK activation and the dissociation of Beclin 1 from the Beclin 1/Bcl-2 complex) [179], AKT inhibitor 1/2 (AKTi-1/2) in vitro and in vivo [180], doxorubicin [181], indicating that autophagy inhibition could be an effectual approach in combination therapy to overcome chemoresistance in HCC. Moreover, the study also revealed that the BMP4 induced autophagy was mediated through activating the JNK1/Bcl2 pathway [182].…”

Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma

“…Combination therapy of chloroquine and doxorubicin exhibits increased anti-tumor activity in HCC models [49]. In addition to chemical inhibitors of autophagy, few bioactive strategies including red ginseng extract have been shown to inhibit cytoprotective autophagy and sensitize HCC cells to therapy [50]. Interestingly, sorafenib induces autophagy in HCC cells compromising its efficacy but wogonin, (5,7-dihydroxy-8-methoxyflavone), a flavonoid derived from the root of the medicinal herb Scutellaria baicalensis , effectively inhibits sorafenib-induced autophagy and combining sorafenib with wogonin yields better efficacy [51].…”

Autophagy and its regulation by ginseng components

“…On the other hand, RGE inhibited autophagic flux synergistically with doxorubicin, leading to cell death in hepatocarcinoma cell lines [36]. RGE-mediated prevention of autophagic flux increased the sensitivity of the cancer cells to the doxorubicin.…”