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Resveratrol induces cell-cycle disruption and apoptosis in chemoresistant B16 melanoma
Grégory Gatouillat1, Emilie Balasse, Débora Joseph-Pietras
1Faculty of Pharmacy, Department of Biochemistry and Molecular Biology, URCA, Reims, France.
Abstract:
Resveratrol, a naturally occurring polyphenol, has been shown to possess chemopreventive activities. In this study, we show that resveratrol (0-500 microM) inhibits the growth of a doxorubicin-resistant B16 melanoma cell subline (B16/DOX) (IC(50) = 25 microM after 72 h, P < 0.05). This was accomplished by imposing an artificial checkpoint at the G(1)-S phase transition, as demonstrated by cell-cycle analysis and down-regulation of cyclin D1/cdk4 and increased of p53 expression level. The G(1)-phase arrest of cell cycle in resveratrol-treated (10-100 microM) B16/DOX cells was followed by the induction of apoptosis, which was revealed by pyknotic nuclei and fragmented DNA. Resveratrol also potentiated at subtoxic dose (25 microM for 24 h) doxorubicin cytotoxicity in the chemoresistant B16 melanoma (P < 0.01). When administered to mice, resveratrol (12.5 mg/kg) reduced the growth of an established B16/DOX melanoma and prolonged survival (32% compared to untreated mice). All these data support a potential use of resveratrol alone or in combination with other chemotherapeutic agents in the management of chemoresistant tumors.
Insights
Resveratrol inhibits the growth of chemoresistant melanoma by halting cell cycle progression and inducing apoptosis. This natural compound also enhances doxorubicin
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Resveratrol, a polyphenol, exhibits chemopreventive properties.
- Chemotherapeutic resistance, particularly to doxorubicin, is a significant clinical challenge in melanoma treatment.
Purpose of the Study:
- To investigate the efficacy of resveratrol against doxorubicin-resistant B16 melanoma.
- To elucidate the mechanisms underlying resveratrol's anti-cancer effects.
- To evaluate resveratrol's therapeutic potential in vivo.
Main Methods:
- Cell culture of doxorubicin-resistant B16 melanoma (B16/DOX) cells.
- Resveratrol treatment and assessment of cell viability (IC50 determination).
- Cell cycle analysis, Western blotting for cyclin D1/cdk4 and p53 expression.
- Apoptosis assays (nuclear morphology, DNA fragmentation).
- In vivo studies using a mouse melanoma model.
Main Results:
- Resveratrol inhibited B16/DOX cell growth with an IC50 of 25 microM.
- Resveratrol induced G1-S phase arrest by down-regulating cyclin D1/cdk4 and up-regulating p53.
- Resveratrol triggered apoptosis in B16/DOX cells.
- Resveratrol potentiated doxorubicin cytotoxicity in chemoresistant melanoma.
- In vivo, resveratrol reduced tumor growth and prolonged survival in mice.
Conclusions:
- Resveratrol demonstrates significant anti-cancer activity against chemoresistant melanoma.
- Resveratrol's mechanism involves cell cycle arrest and apoptosis induction.
- Resveratrol holds potential as a therapeutic agent for chemoresistant melanoma, alone or in combination therapy.
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