Resveratrol and P-glycoprotein Inhibitors Enhance the Anti-Skin Cancer Effects of Ursolic Acid

Abstract

Ursolic acid (UA), present in apples, rosemary, and other sources, is known to inhibit tumor formation and tumor cell viability in multiple systems, including skin. However, various cancers are resistant to UA treatment. Herein, skin carcinoma cells (Ca3/7) as compared to skin papilloma cells (MT1/2) displayed more resistance to UA-induced cytotoxicity. Interestingly, Ca3/7 cells had elevated levels of P-glycoprotein (P-gp), an ATP-dependent efflux pump that mediates resistance to chemotherapy in pre-clinical and clinical settings, and not only accumulated less but also more rapidly expelled the P-gp substrate Rhodamine 123 (Rh123) indicating UA is transported by P-gp. To determine if P-gp inhibition can enhance UA-mediated cytotoxicity, cells were challenged with P-gp inhibitors verapamil (VRP) or cyclosporin A (CsA). Alternatively, cells were pre-treated with the natural compound resveratrol (RES), a known chemotherapy sensitizer. VRP and RES enhanced the effects of UA in both cell lines, while CsA only did so in Ca3/7 cells. Similarly, VRP inhibited Rh123 efflux in both lines, while CsA only inhibited Rh123 efflux in Ca3/7 cells. RES did not inhibit Rh123 efflux in either line, indicating the synergistic effects of RES and UA are not manifest by inhibition of P-gp-mediated efflux of UA. These results indicate that the anti-skin cancer effects of UA are enhanced with P-gp inhibitors. In addition, RES and UA interact synergistically, but not through inhibition of P-gp. Implications Resveratrol and/or p-glycoprotein inhibitors in combination with ursolic acid are an effective anti-skin cancer regimen.

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

“…For example, ursolic acid, asiatic acid, and maslinic acids have been reported to show antitumor properties [4-6]. Recently, many studies revealed that some triterpenoids, such as ursolic acid and oleanolic acid, are P-glycoprotein inhibitors and reverse multidrug resistance (MDR) in cancer cells [7-8]. …”

Effect of Combined Treatment with Ursolic Acid and Resveratrol on Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate

“…Recently, Junco et al . reported that Res potentiates the growth inhibitory effect of UA in mouse skin papilloma and carcinoma cell lines (25). Thus, combining agents may provide the most rational and effective approach to cancer chemoprevention.…”

Role of AMPK and PPARα in the anti‐skin cancer effects of ursolic acid

“…P‐glycoprotein is a drug‐effluxing pump which contributes to chemoresistance to a wide variety of xenobiotics, including anti‐cancer compounds . In addition, our recent studies show that the cytotoxic effects of UA are enhanced with inhibition of p‐glycoprotein . In our system, RU486 may decrease the basal expression of p‐glycoprotein resulting in increased intracellular UA and enhanced cytotoxicity .…”

“…The natural phytonutrient ursolic acid (UA) has been shown to have both anti‐cancer and anti‐diabetic effects in a variety of in vitro and in vivo systems. A number of studies indicated UA activates the energy sensor AMP‐activated protein kinase (AMPK), which has both anti‐cancer and anti‐diabetic properties.…”