Inhibitory Effects of Oligostilbenoids from the Bark of <i>Shorea roxburghii</i> on Malignant Melanoma Cell Growth: Implications for Novel Topical Anticancer Candidates

Abstract

Human malignant melanomas remain associated with dismal prognosis due to their resistance to apoptosis and chemotherapy. There is growing interest in plant oligostilbenoids owing to their pleiotropic biological activities, including anti-inflammatory, antioxidant, and anticancer effects. Recent studies have demonstrated that resveratrol, a well-known stilbenoid from red wine, exhibits cell cycle-disrupting and apoptosis-inducing activities on melanoma cells. The objective of our study was to evaluate the anti-melanoma effect of oligostilbenoids isolated from the bark of Shorea roxburghii. Among the isolates, four resveratrol oligomers, i.e., ( )-hopeaphenol, vaticanol B, hemsleyanol D, and ( )-α-viniferin, possessed more potent antiproliferative action than did resveratrol against SK-MEL-28 melanoma cells. Cell cycle analysis revealed that ( )-hopeaphenol, hemsleyanol D, and ( )-α-viniferin arrested cell division cycle at the G1 phase, whereas vaticanol B had little effect on the cell cycle. In addition, cell proliferation assay also revealed that ( )-α-viniferin induced DNA damage followed by induction of apoptosis in SK-MEL-28 cells, which was confirmed by an increased expression of γ-H2AX and cleaved caspase-3, respectively. The compounds vaticanol B, hemsleyanol D, and resveratrol significantly increased the expression of p21, suggesting that they are able to block cell cycle progression. Moreover, these oligostilbenoids downmodulated cylin D1 expression and extracellular signal-regulated kinase (ERK) activation. Furthermore, hemsleyanol D, ( )-α-viniferin, and resveratrol significantly decreased the expression of cyclin B1, which could also suppress cell cycle progression. The present study thus suggests that these plant oligostilbenoids are effective as therapeutic or chemopreventive agents against melanoma.

Gnetin‐C and other resveratrol oligomers with cancer chemopreventive potential

“…Hopeaphenol inhibits topoisomerase IIA and MOS1 transposase . In in vitro studies, this compound inhibited the growth of SK‐MEL‐28 melanoma cells, D‐GBM glioblastoma cells, P‐388 leukemia cells, and the epidermoid carcinoma line KB . In a mouse study, hopeaphenol significantly attenuated tumor formation by sarcoma S‐180 cells that had been subcutaneously allografted into DDY mice.…”

Shorea roxburghii Leaf Extract Ameliorates Hyperglycemia Induced Abnormalities in High Fat/Fructose and Streptozotocin Induced Diabetic Rats

“…Previous phytochemical investigation showed that the stem back and roots of S. roxburghii are composed of phenolic constituents mainly stilbenoids, oligostilbenoids and dihydroisocoumarins. These compounds have displayed several pharmacological functions including cytotoxic, hepatoprotective, antihyperlipidemic, anticancer, antidiabetogenic, antiproliferative and antioxidant properties . However, to the best of our knowledge, there are no reported studies on the chemical components or pharmacological effects of the leaves of S. roxburghii .…”

An update on the implications of cyclin D1 in melanomas

“…(I) It may also be possible to use general CDK inhibitors (flavopiridol, olomoucine, or R-roscovitine) or (J) selective CDK4/6 inhibitors (abemaciclib [LY2835219], palbociclib [PD0332991], or ribociclib [LEE011]). (K) Finally, the combination of BRaf inhibitors with CDK4/6 inhibitors (e.g., palbociclib and vemurafenib) is currently under clinical trial, with reports that it may overcome acquired resistance to treatment based on anti-BRaf inhibitors alone and may offer greater effectiveness than the sum of each therapy individually (Arioka et al, 2017;Ashford et al, 2014;Costantino et al, 2016;Daveri, Valacchi, Romagnoli, Maellaro, & Maioli, 2015;Diehl, Cheng, Roussel, & Sherr, 1998;Ferreira et al, 2016;Fofaria, Kim, & Srivastava, 2014;Kuang et al, 2018;Lavhale, Kumar, Mishra, & Sitasawad, 2009;Li, Wang, & Yan, 2017;Li et al, 2016;Ma, Liu, Qi, & Zhang, 2014;Malyarenko et al, 2017;Matsuzaki et al, 2008;Moriyama, Moriyama, Ninomiya, Morikawa, & Hayakawa, 2016;Nihal, Ahmad, Mukhtar, & Wood, 2005;Nivelle et al, 2018;Park, 2014;Pratheeshkumar & Kuttan, 2011;Siveen & Kuttan, 2011;Sonoda et al, 2008;Tsubaki et al, 2015;Wang, Zhang, Zhang, & Sanderson, 2013;Wang, Xu, et al, 2013;Yokota et al, 2007;You et al, 2017; Table 1).…”