3,3′,4,4′,5,5′-Hexahydroxystilbene Impairs Melanoma Progression in a Metastatic Mouse Model

Abstract

Stilbenes comprise a group of polyphenolic compounds, which exert inhibitory effects on various malignancies. The aim of this study was to evaluate the antitumor effects of a previously unreported stilbene derivative-3,3',4,4',5,5'-hexahydroxystilbene, termed M8-on human melanoma cells. Cell-cycle analysis of the metastatic melanoma cell line M24met showed that M8 treatment induces G(2)/M arrest accompanied with a dose- and time-dependent upregulation of p21 and downregulation of CDK-2 and leads to apoptosis. M8 induces the expression of phosphorylated p53, proteins involved in the mismatch repair machinery (MSH6, MSH2, and MLH1) and a robust tail moment in a comet assay. In addition, M8 inhibited cell migration in Matrigel assays. Shotgun proteomics and western analysis showed the regulation among others of paxillin, integrin-linked protein kinase, p21-activated kinase, and ROCK-1 indicating that M8 inhibits mesenchymal and amoeboid cell migration. These in vitro data were confirmed in vivo in a metastatic human melanoma severe combined immunodeficient (SCID) mouse model. We showed that M8 significantly impairs tumor growth. M8 also interfered with the metastatic process, as M8 treatment prevented the metastatic spread of melanoma cells to distant lymph nodes in vivo. In summary, M8 exerts strong antitumor effects with the potential to become a new drug for the treatment of metastatic melanoma.

Resveratrol and its synthetic derivatives exert opposite effects on mesothelial cell-dependent angiogenesis via modulating secretion of VEGF and IL-8/CXCL8

“…On the other hand, our results pointing on the pro-angiogenic effects of RVT analogues should be considered with caution by those who working on these compounds (e.g. 3,3′,4,4′,5,5′-HHS) uncritically suggest their usefulness in the anti-cancer therapy [42, 43, 59]. The threat associated with the use of these stilbenes is related to stimulation of angiogenesis, especially in tissues which are known to accumulate senescent cells.…”

Synthetic Resveratrol Analogue, 3,3',4,4',5,5'-Hexahydroxy-trans-Stilbene, Accelerates Senescence in Peritoneal Mesothelium and Promotes Senescence-Dependent Growth of Gastrointestinal Cancers

“…For instance, the proliferation assays performed on various types of breast cancer cells treated with M8 revealed that IC 50 values for this stilbene range from 90 to 127 μM [12]. In studies on melanoma cells, IC 50 was between 20 and 25 μM [15]. Similar tendency was reported in the case of apoptotic potency of M8 which achieved the values near to maximal (100%) at the doses from 12.5 to 100 μM [13].…”

“…These studies are based on a paradigm that an introduction of additional groups into the stilbene structure strengthens biological properties of RVT analogues [11]. Of these newly synthesized derivatives, high expectations are linked with 3,3′,4,4′,5,5′-hexahydroxy- trans -stilbene (M8) which has been found to inhibit growth and/or induce apoptosis in various malignancies, including breast and colon cancers [12,13], leukemia [14], melanoma [15], and glioma cells [16] (Figure 1). …”

Phytochemicals for the Management of Melanoma

“…Furthermore, hexahydroxystilbene (M8) inhibited cell migration in matrigel assays. In addition, hexahydroxystilbene (M8) inhibited melanoma tumor growth and prevented metastasis of melanoma cells to distant lymph nodes in the SCID mouse model [177–179]. Monohydroxylated resveratrol (also, piceatannol) possesses better anti-tumor activity than resveratrol itself and is a potent COX-2 inhibitor.…”