Abstract
Ursolic acid, present in apples, rosemary, and other sources, is known to inhibit tumor formation and tumor cell viability inmultiple systems, including skin. However, various cancers are resistant to ursolic acid treatment. Herein, skin carcinoma cells (Ca3/7) as compared with skin papilloma cells (MT1/2) displayed more resistance to ursolic acid-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 preclinical and clinical settings, and not only accumulated less but also more rapidly expelled the P-gp substrate rhodamine 123 (Rh123) indicating ursolic acid is transported by P-gp. To determine whether P-gp inhibition can enhance ursolic acid-mediated cytotoxicity, cells were challenged with P-gp inhibitors verapamil or cyclosporin A. Alternatively, cells were pretreated with the natural compound resveratrol, a known chemotherapy sensitizer. Verapamil and resveratrol enhanced the effects of ursolic acid in both cell lines, whereas cyclosporin A only did so in Ca3/7 cells. Similarly, verapamil inhibited Rh123 efflux in both lines, whereas cyclosporin A only inhibited Rh123 efflux in Ca3/7 cells. Resveratrol did not inhibit Rh123 efflux in either line, indicating the synergistic effects of resveratrol and ursolic acid are not manifest by inhibition of P-gp-mediated efflux of ursolic acid. These results indicate that the anti-skin cancer effects of ursolic acid are enhanced with P-gp inhibitors. In addition, resveratrol and ursolic acid 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1521-1529 |
| Number of pages | 9 |
| Journal | Molecular Cancer Research |
| Volume | 11 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2013 |
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ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Oncology
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Resveratrol and P-glycoprotein inhibitors enhance the anti-skin cancer effects of ursolic acid. / Junco, Jacob J.; Mancha, Anna; Malik, Gunjan; Wei, Sung Jen; Kim, Dae Joon; Liang, Huiyun; Slaga, Thomas J.
In: Molecular Cancer Research, Vol. 11, No. 12, 12.2013, p. 1521-1529.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Resveratrol and P-glycoprotein inhibitors enhance the anti-skin cancer effects of ursolic acid
AU - Junco, Jacob J.
AU - Mancha, Anna
AU - Malik, Gunjan
AU - Wei, Sung Jen
AU - Kim, Dae Joon
AU - Liang, Huiyun
AU - Slaga, Thomas J
PY - 2013/12
Y1 - 2013/12
N2 - Ursolic acid, present in apples, rosemary, and other sources, is known to inhibit tumor formation and tumor cell viability inmultiple systems, including skin. However, various cancers are resistant to ursolic acid treatment. Herein, skin carcinoma cells (Ca3/7) as compared with skin papilloma cells (MT1/2) displayed more resistance to ursolic acid-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 preclinical and clinical settings, and not only accumulated less but also more rapidly expelled the P-gp substrate rhodamine 123 (Rh123) indicating ursolic acid is transported by P-gp. To determine whether P-gp inhibition can enhance ursolic acid-mediated cytotoxicity, cells were challenged with P-gp inhibitors verapamil or cyclosporin A. Alternatively, cells were pretreated with the natural compound resveratrol, a known chemotherapy sensitizer. Verapamil and resveratrol enhanced the effects of ursolic acid in both cell lines, whereas cyclosporin A only did so in Ca3/7 cells. Similarly, verapamil inhibited Rh123 efflux in both lines, whereas cyclosporin A only inhibited Rh123 efflux in Ca3/7 cells. Resveratrol did not inhibit Rh123 efflux in either line, indicating the synergistic effects of resveratrol and ursolic acid are not manifest by inhibition of P-gp-mediated efflux of ursolic acid. These results indicate that the anti-skin cancer effects of ursolic acid are enhanced with P-gp inhibitors. In addition, resveratrol and ursolic acid 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.
AB - Ursolic acid, present in apples, rosemary, and other sources, is known to inhibit tumor formation and tumor cell viability inmultiple systems, including skin. However, various cancers are resistant to ursolic acid treatment. Herein, skin carcinoma cells (Ca3/7) as compared with skin papilloma cells (MT1/2) displayed more resistance to ursolic acid-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 preclinical and clinical settings, and not only accumulated less but also more rapidly expelled the P-gp substrate rhodamine 123 (Rh123) indicating ursolic acid is transported by P-gp. To determine whether P-gp inhibition can enhance ursolic acid-mediated cytotoxicity, cells were challenged with P-gp inhibitors verapamil or cyclosporin A. Alternatively, cells were pretreated with the natural compound resveratrol, a known chemotherapy sensitizer. Verapamil and resveratrol enhanced the effects of ursolic acid in both cell lines, whereas cyclosporin A only did so in Ca3/7 cells. Similarly, verapamil inhibited Rh123 efflux in both lines, whereas cyclosporin A only inhibited Rh123 efflux in Ca3/7 cells. Resveratrol did not inhibit Rh123 efflux in either line, indicating the synergistic effects of resveratrol and ursolic acid are not manifest by inhibition of P-gp-mediated efflux of ursolic acid. These results indicate that the anti-skin cancer effects of ursolic acid are enhanced with P-gp inhibitors. In addition, resveratrol and ursolic acid 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.
UR - http://www.scopus.com/inward/record.url?scp=84891356413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891356413&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-13-0237
DO - 10.1158/1541-7786.MCR-13-0237
M3 - Article
C2 - 24072817
AN - SCOPUS:84891356413
VL - 11
SP - 1521
EP - 1529
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 12
ER -