Activation of ERK1/2 is required for the antimitotic activity of the resveratrol analogue 3,4,5,4′‐tetramethoxystilbene (DMU‐212) in human melanoma cells

Androutsopoulos, Vasilis P.; Fragiadaki, Irene; Tosca, Androniki

doi:10.1111/exd.12721

Cited by 19 publications

(14 citation statements)

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“…shown to possess promising anti-proliferative activity in vitro in breast, ovarian and colon cancer cells (10,11,14,15). Recently, we published a study that demonstrates the efficacy of 3,4,5,4'-TMS in human melanoma in vitro (12). In the present study, the results of the latter study were verified.…”

Section: 454'-tms Inhibits the Growth Of A375 Melanoma Cells At Msupporting

confidence: 72%

“…The resveratrol analogue, 3,4,5,4'-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action 3,4,5,4'-TMS has been shown to exert more potent inhibitory effects than resveratrol on the proliferation of cancer cells in vitro, whereas the anti-proliferative action of the compound is attributed to the induction of apoptosis and cell cycle arrest (10,11). A recent study conducted by our group demonstrated that 3,4,5,4'-TMS may effectively inhibit the proliferation of human melanoma cells by inducing apoptosis and cell cycle arrest, through the activation of the mitogen-activated protein kinase (MAPK), ERK1/2 (12). In the present study, the activation of the MAPK protein, p38, by 3,4,5,4'-TMS was investigated using A375 human melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

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The resveratrol analogue, 3,4,5,4′-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action

Androutsopoulos

Fragiadaki

Spandidos

et al. 2016

International Journal of Oncology

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Resveratrol is a natural dietary product that has demonstrated multifaceted anticancer activity. Several analogues of resveratrol have been synthesized in an effort to enhance the pharmacological potency and improve the pharmacokinetic properties of the compound. 3,4,5,4'‑trans‑tetramethoxystilbene (3,4,5,4'‑TMS) is a methoxylated analogue of resveratrol that has demonstrated anti-proliferative activity in vitro (in cancer cell lines) and in vivo (in xenograft models). In the present study, the anticancer effects of 3,4,5,4'‑TMS in A375 human melanoma cells were examined. 3,4,5,4'‑TMS markedly inhibited the proliferation of A375 cells (IC50=0.7 µM), via a mechanism involving mitotic arrest at the prometaphase stage of cell division. This effect was accompanied by the upregulation of the expression of the mitogen activated protein kinases, JNK and p38, and the concomitant activation of p38, that was verified by the nuclear translocation of the phoshorylated form of the protein. The pharmacological inhibition of p38 by SB203580 (4 µM) attenuated the effects of 3,4,5,4'‑TMS, as demonstrated by decreased cell cycle progression at the mitotic phase. Furthermore, 3,4,5,4'‑TMS increased the total levels of Aurora A, while it inhibited the localization of the protein to the spindle poles. Finally, 3,4,5,4'‑TMS exhibited anti-metastatic activity, inhibiting A375 cell migration and the attachment of the cells to a collagen type IV-coated surface. Collectively, the data suggest that 3,4,5,4'‑TMS is an effective chemotherapeutic drug for the treatment of human melanoma and that it exerts its effects through multiple anticancer modes of action.

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Section: 454'-tms Inhibits the Growth Of A375 Melanoma Cells At Msupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

The resveratrol analogue, 3,4,5,4′-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action

Androutsopoulos

Fragiadaki

Spandidos

et al. 2016

International Journal of Oncology

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“…Furthermore, methylated resveratrol analogues bearing -OMe groups at positions 3,5- and 3,4,5- of the trihydroxystilbene moiety have been reported to demonstrate stronger pro-apoptotic activity when compared to other stilbene derivatives5. One such molecule, DMU-212 (3,4,5,4′-tetramethoxystilbene), has been revealed to have anti-cancer activity via cell cycle arrest and activation of apoptosis6789101112.…”

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confidence: 99%

3′-hydroxy-3,4,5,4′-tetramethoxystilbene, the metabolite of resveratrol analogue DMU-212, inhibits ovarian cancer cell growth in vitro and in a mice xenograft model

Piotrowska‐Kempisty

Ruciński

Borys

et al. 2016

Sci Rep

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In screening studies, the cytotoxic activity of four metabolites of resveratrol analogue 3,4,5,4′-tetramethoxystilbene (DMU-212) against A-2780 and SKOV-3 ovarian cancer cells was investigated. The most active metabolite, 3′-hydroxy-3,4,5,4′-tetramethoxystilbene (DMU-214), was chosen for further studies. The cytotoxicity of DMU-214 was shown to be higher than that of the parent compound, DMU-212, in both cell lines tested. Since DMU-212 was supposed to undergo metabolic activation through its conversion to DMU-214, an attempt was made to elucidate the mechanism of its anti-proliferative activity. We found that in SKOV-3 cells lacking p53, DMU-214 induced receptor-mediated apoptosis. In A-2780 cell line with expression of wild-type p53, DMU-214 modulated the expression pattern of p53-target genes driving intrinsic and extrinsic apoptosis pathways, as well as DNA repair and damage prevention. Regardless of the up-regulation of p48, p53R2, sestrins and Gaad45 genes involved in cancer cell DNA repair, we demonstrated the stronger anti-proliferative and pro-apoptotic effects of DMU-214 in A-2780 cells when compared to those in SKOV-3. Hence we verified DMU-214 activity in the xenograft model using SCID mice injected with A-2780 cells. The strong anti-proliferative activity of DMU-214 in the in vivo model allowed to suggest the tested compound as a potential therapeutic in ovarian cancer treatment.

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“…Studies using human melanoma cells demonstrated that 3,4,5,4′-tetramethoxystilbene (DMU-212) (Fig. 4F) exerts it anti-mitotic effect by ERK1/2 activation [181]. Moreover studies have demonstrated that methylation at key positions of the cis-resveratrol (Fig.…”

Section: Phytochemicals For the Prevention/treatment Of Melanomamentioning

confidence: 99%

Phytochemicals for the Management of Melanoma

Pal¹,

Hunt²,

Diamond³

et al. 2016

MRMC

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Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.

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Activation of ERK1/2 is required for the antimitotic activity of the resveratrol analogue 3,4,5,4′‐tetramethoxystilbene (DMU‐212) in human melanoma cells

Cited by 19 publications

References 15 publications

The resveratrol analogue, 3,4,5,4′-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action

The resveratrol analogue, 3,4,5,4′-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action

3′-hydroxy-3,4,5,4′-tetramethoxystilbene, the metabolite of resveratrol analogue DMU-212, inhibits ovarian cancer cell growth in vitro and in a mice xenograft model

Phytochemicals for the Management of Melanoma

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