Discovery of novel peptide-dehydroepiandrosterone hybrids inducing endoplasmic reticulum stress with effective in vitro and in vivo anti-melanoma activities.

Steroid hybrids have emerged as a type of advantageous compound as they could offer improved pharmacological and pharmaceutical properties. Here, we report a series of novel peptide-dehydroepiandrosterone hybrids, which would effectively induce endoplasmic reticulum stress (ERS) and lead to apoptosis with outstanding in vitro and in vivo anti-melanoma effects. The lead compound IId among various steroids conjugated with peptides and pyridines showed effective in vivo activity in B16 xenograft mice: in medium- and high-dose treatment groups (60 and 80 mg/kg), compound IId would significantly inhibit the growth of tumours by 98%-99% compared to the control group, with the highest survival rate as well. Further mechanism studies showed that compound IId would damage the endoplasmic reticulum and upregulate the ERS markers C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), which could further regulate caspase and Bcl-2 family proteins and lead to cell apoptosis. The compound IId was also proven to be effective in inhibiting B16 cell migration and invasion.

A LY-15, a novel cyclic pentapeptide that inhibits B16 cell proliferation and migration and induces cell apoptosis.

Melanoma is highly resistant to most traditional treatments; therefore, its incidence and mortality rates are rapidly increasing. The effect of a novel sansalvamide A analogue named LY-15 on the growth and induction of apoptosis in B16 cancer cells was investigated in vitro. The inhibitory effects of LY-15 on B16 cells occurred in a concentration- and time-dependent manner. The B16 cells were cultured in various concentrations of LY-15 (5, 15 and 25 µM), and the ameliorating effect of LY-15 was evaluated using apoptotic protein markers B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3 and caspase-9. Furthermore, LY-15 effectively inhibited the B16 cell migration, increased the expressions levels of caspase-3, caspase-9 and the pro-apoptotic Bax, and reduced that of the anti-apoptotic Bcl-2. These findings suggested that LY-15 is a promising chemotherapeutic agent against melanoma by inducing apoptosis through the mitochondrial-associated death pathway. In addition, sansalvamide A analogue LY-15 may a significant therapeutic target for the treatment of malignant melanoma cancer.