Abstract
In this study the isolated compound 11-dehydrosinulariolide from soft coral Sinularia leptoclados possessed anti-proliferative, anti-migratory and apoptosis-inducing activities against A2058 melanoma cells. Anti-tumor effects of 11-dehydrosinulariolide were determined by MTT assay, cell migration assay and flow cytometry. Growth and migration of melanoma cells were dose-dependently inhibited by 2–8 μg/mL 11-dehydrosinulariolide. Flow cytometric data indicated that 11-dehydrosinulariolide induces both early and late apoptosis in melanoma cells. It was found that the apoptosis induced by 11-dehydrosinulariolide is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome C, activation of caspase-3/-9 and Bax as well as suppression of Bcl-2/Bcl-xL. The cleavage of PARP-1 suggested partial involvement of caspase-independent pathways. Immunoblotting data displayed up-regulations of PERK/eIF2α/ATF4/CHOP and ATF6/CHOP coupling with elevation of ER stress chaperones GRP78, GRP94, calnexin, calreticulin and PDI, implicating the involvement of these factors in ER stress-mediated apoptosis induced by 11-dehydrosinulariolide. The abolishment of apoptotic events after pre-treatment with salubrinal indicated that ER stress-mediated apoptosis is also induced by 11-dehydrosinulariolide against melanoma cells. The data in this study suggest that 11-dehydrosinulariolide potentially induces apoptosis against melanoma cells via mitochondrial dysregulation and ER stress pathways.
Highlights
Melanoma is a malignant tumor of cutaneous melanocytes
The data of MTT assay showed that proliferation of A2058 melanoma cells was dose-dependently inhibited by 2 to 8 μg/mL of 11-dehydrosinulariolide
Cell migration data displayed that 2–6 μg/mL 11-dehydrosinulariolide suppressed melanoma cell migration in a dose-dependent manner as the suppression rates were approximately 32%, 51% and 73% for 2, 4 and 6 μg/mL of 11-dehydrosinulariolide treatment, respectively (Figure 1)
Summary
Melanoma is a malignant tumor of cutaneous melanocytes. Incidence of melanoma is usually lower than other skin cancers such as basal cell cancer and squamous cell cancer. Surgery is still the most effective measure for malignant melanoma patients with small and thin neoplastic lesions [6]. The survival rate is dependent on the diagnostic stage of melanoma [7]. Other medical treatments such as chemotherapy (with dacarbazine) and immunotherapy (with interleukin-2 or interferon) have been investigated [8,9,10]. Their achievements clinically applied in metastatic melanoma are still limited [11]. It is necessary to investigate and discover new effective drugs and therapies against human malignant melanoma
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