Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells.

Saniya Ossikbayeva,Richard Sensenig,Slava Rom,Aviram Trachtenberg,Zulfiya Orynbayeva,Sultan Tuleukhanov,Michael Danilenko,Yoav Sharoni,Marina Khanin

doi:10.3390/antiox10101591

Abstract

Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G0/G1 cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality.

Highlights

Phytochemicals have been one of the major foundations of drug development [1]
We examined whether the two polyphenols (CUR and carnosic acid (CA)) applied at similar low concentrations (≤10 μM) would synergize in inducing apoptotic cell death of DU145 and PC-3 cells, the most widely studied human metastatic prostate cancer cell lines [35]
Towe examined whether the effects of the combination on respiration of prostate test this, we examined whether the effects of the CUR + CA combination on respiration of cancercancer cells are influenced by rapamycin

Summary

Introduction

Phytochemicals have been one of the major foundations of drug development [1]. That are difficult to reach in vivo due to a low bioavailability and extensive metabolism of this polyphenol [15,16]. At such concentrations CUR has been found to induce geno/cytotoxicity to at least some types of normal cells [17,18,19,20,21]. Combinations of CUR with different phytochemicals or drugs have demonstrated enhanced anticancer effects in various models of human malignancies, as compared to single agents (see [22,23,24] for recent reviews). Pairing CUR with the polyphenols quercetin [25], resveratrol [26,27], epigallocatechin gallate [28] or ursolic acid [29]

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Conclusion