2‐phenylethynesulphonamide (PFT‐μ) enhances the anticancer effect of the novel hsp90 inhibitor NVP‐AUY922 in melanoma, by reducing GSH levels

Abstract

Heat shock proteins (HSPs), are molecular chaperones that assist the proper folding of nascent proteins. This study aims to evaluate the antitumour effects of the hsp90 inhibitor NVP-AUY922 in melanoma, both in vitro and in vivo. Our results show that NVP-AUY922 inhibits melanoma cell growth in vitro, with down regulation of multiple signalling pathways involved in melanoma progression such as NF-ĸB and MAPK/ERK. However, NVP-AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP-AUY922 and PFT-μ, a dual inhibitor of both hsp70 and autophagy, induced a synergistic increase of cell death in vitro, and delayed tumour formation in A375M xenografts. PFT-μ depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT-μ further enhanced NVP-AUY922-induced cytotoxic effects. These data suggest a potential therapeutic role for NVP-AUY922 used in combination with PFT-μ, in melanoma.

Inhibitors of HSP90 in melanoma

“…NVP-AUY922 affected proliferation and inhibited colony-forming capacity of melanoma cells. NVP-AUY922 decreased protein level of cyclin D1, and decreased activity of ERK1/2 and NF-κB signaling pathway [117]. In addition to inducing apoptosis, NVP-AUY922 elevated LC3II/LC3I (microtubule-associated proteins 1A/1B light chain 3B) ratio in a time-dependent manner indicating activation of autophagy [117].…”

“…NVP-AUY922 decreased protein level of cyclin D1, and decreased activity of ERK1/2 and NF-κB signaling pathway [117]. In addition to inducing apoptosis, NVP-AUY922 elevated LC3II/LC3I (microtubule-associated proteins 1A/1B light chain 3B) ratio in a time-dependent manner indicating activation of autophagy [117]. Conflicting results of NVP-AUY922 activity on melanoma tumor growth and metastasis were published [116,117].…”

“…In addition to inducing apoptosis, NVP-AUY922 elevated LC3II/LC3I (microtubule-associated proteins 1A/1B light chain 3B) ratio in a time-dependent manner indicating activation of autophagy [117]. Conflicting results of NVP-AUY922 activity on melanoma tumor growth and metastasis were published [116,117]. NVP-AUY922 induced expression of HSP70, GRP78 and DDIT3 (DNA damage-inducible transcript 3) encoding CHOP, thereby increasing endoplasmic reticulum stress and activating unfolded protein response in melanoma cells [117].…”

Autophagy: In the cROSshairs of cancer

“…As an alternative approach to antioxidant supplementation, the employment of antioxidant-depleting strategies has resulted in considerable higher efficacy in melanoma through excessive ROS generation and cell death [41, 42]. For example, downregulation of the NRF2 antioxidant defense pathway has shown marked anti-melanoma activity [43]. Additionally, depletion of the glutathione system in melanoma appears to have marked success in potentiating a pro-apoptotic response, as the accumulation of ROS leads to melanoma inhibition both in vitro and in vivo [44, 45].…”

“…Cell fate outcomes are largely dependent on the amount of ROS generated and the cell’s antioxidant response. A summary of studies that examine the effect of dual modulation of ROS and autophagy on melanoma preclinical and clinical outcomes is presented in Table 3 [43, 76, 85, 96-100]. …”