Resveratrol induces SIRT1- and energy–stress-independent inhibition of tumor cell regrowth after low-dose platinum treatment
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To investigate resveratrol (RSV) as a calorie restriction (CR) mimetic potentiator of platinum-based cancer drugs.
In ovarian carcinoma cell lines, the potentiating effects of RSV were assessed in sulforhodamine B-based growth assays and clonogenic assays. Flow cytometry was used to detect cell cycle effects, siRNA transfections for determining the involvement of SIRT1, and Western blotting for the assessment of altered protein expression and of autophagy. Intracellular ATP levels were detected with a commercial kit.
Single-dose RSV co-treatment with cisplatin or carboplatin at inefficiently low doses had the clinically interesting effect of preventing regrowth of cancer cells after drug withdrawal. Of three cell lines tested, metastatic cells with low bioenergetic cellular index (i.e., more glycolytic) were particularly sensitive to combination treatment leading to PUMA induction, acute apoptosis, and autophagy. However, inhibition of regrowth and complete loss of clonogenicity was seen also without these events, in other cells. The underlying mechanism(s) was independent of effects reported to underlie the CR-mimetic cancer-preventive potential of RSV. Thus, SIRT1, estrogen receptors, AMPK activation or upregulation of mitobiogenesis, β-F1-ATPase or PTEN were not involved, and ATP levels did not decrease.
RSV is an excellent candidate for potentiation of platinum treatment, rather than a cancer therapeutic drug in its own right. While SIRT1-dependent and lifespan-promoting effects of RSV are well-documented and may dominate in normal cells, the observed potentiation of platinum drugs does not require these mechanisms. We suggest that the responses of cancer cells to RSV differ greatly from those of normal cells.
KeywordsChemotherapy Platinum Resveratrol SIRT1 Ovarian carcinoma
This study was supported by the Swedish Cancer Society, Radiumhemmet Research Foundation, Olle Engkvist Byggmästare and Sigurd and Elsa Golje Foundations. Linnéa Björklund is gratefully acknowledged for photography, and Drs. Theocharis Panaretakis and Pedram Kharaziha for technical advice.
Conflict of interest
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