Apoptosis Induced by Ginkgo biloba (EGb761) in Melanoma Cells Is Mcl-1-Dependent

Abstract

Melanoma is an aggressive skin cancer. Unfortunately, there is currently no chemotherapeutic agent available to significantly prolong the survival of the most patients with metastatic melanomas. Here we report that the Ginkgo biloba extract (EGb761), one of the most widely sold herbal supplements in the world, potently induces apoptosis in human melanoma cells by disturbing the balance between pro- and anti-apoptosis Bcl-2 family proteins. Treatment with EGb761 induced varying degrees of apoptosis in melanoma cell lines but not in melanocytes. Induction of apoptosis was caspase-dependent and appeared to be mediated by the mitochondrial pathway, in that it was associated with reduction in mitochondrial membrane potential and activation of Bax and Bak. Although EGb761 did not cause significant change in the expression levels of the BH3-only Bcl-2 family proteins Bim, Puma, Noxa, and Bad, it significantly downregulated Mcl-1 in sensitive but not resistant melanoma cells, suggesting a major role of Mcl-1 in regulating apoptosis of melanoma cells induced by EGb761. Indeed, siRNA knockdown of Mcl-1 enhanced EGb761-induced apoptosis, which was associated with increased activation of Bax and Bak. Taken together, these results demonstrate that EGb761 kills melanoma cells through the mitochondrial apoptotic pathway, and that Mcl-1 is a major regulator of sensitivity of melanoma cells to apoptosis induced by EGb761. Therefore, EGb761 with or without in combination with targeting Mcl-1 may be a useful strategy in the treatment of melanoma.

Ginkgo biloba extract protects human melanocytes from H2O2‐induced oxidative stress by activating Nrf2

“…In the present study, we initially found that EGb761 showed no toxic effect on PIG1 cells (data not shown), which was consistent with previous studies . The patients with vitiligo have inferior capacity against oxidative stress due to the lower activity of SOD and GSH‐Px .…”

“…One study reported that EGb761 could protect melanocytes against oxidative stress by activating antioxidase and inhibiting endoplasmic reticulum stress . However, some other studies have controversial findings that Ginkgo biloba or its principal components could induce the apoptosis of melanoma cells . Notably, several clinical trials have illustrated that the application of Ginkgo biloba extract can prevent the onset and the progression of vitiligo, indicating its therapeutic potential in treating vitiligo .…”

“…8 However, some other studies have controversial findings that Ginkgo biloba or its principal components could induce the apoptosis of melanoma cells. 9,10 Notably, several clinical trials have illustrated that the application of Ginkgo biloba extract can prevent the onset and the progression of vitiligo, indicating its therapeutic potential in treating vitiligo. 11 However, the exact mechanism underlying the effect of EGb761 on vitiligo remains unclear.…”

Nickel oxide nanoparticles exert selective toxicity on skin mitochondria and lysosomes isolated from the mouse model of melanoma

“…We showed that NiO‐NPs injection decreased the ATP level in isolated melanoma mitochondria. Various investigations have shown that apoptosis signaling is suppressed in melanoma, and this is one of the failure factors in the treatment of tumor …”

The protective mechanism of Ginkgolides and Ginkgo flavonoids on the TNF-α induced apoptosis of rat hippocampal neurons and its mechanisms in vitro

“…The research of Ginkgolides and Ginkgo flavonoids focus on three aspects: the protective neurons from apoptosis under different conditions [30] [31] [32] , inducing tumor cells apoptosis to exert protective effect [33] [34] [35] , inhibiting apoptosis of cardiomyocytes and endothelial cells (ECs) under hypoxia then exerts a potent protective effect [36] [37] . This paper demonstrated that Ginkgolides and Ginkgo flavonoids might protect hippocampal neurons from apoptosis and explore the possible mechanism.…”