logo

Sildenafil Enhances the Anticancer Activity of Paclitaxel in an ABCB1-Mediated Multidrug Resistance Xenograft Mouse Model

Authors

  • Kamlesh Sodani

    Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA

  • Amit K. Tiwari

    Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA

  • Chun-Ling Dai

    State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People’s Republic of China

  • Alaa H. Abuznait

    Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana, Monroe, Monroe, LA 71201, USA

  • Atish Patel

    Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA

  • Zhi-Jie Xiao

    Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA

  • Charles R. Ashby

    Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA

  • Amal Kaddoumi

    Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana, Monroe, Monroe, LA 71201, USA

  • Li-Wu Fu

    State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, People’s Republic of China

  • Zhe-Sheng Chen

    Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA

DOI:

https://doi.org/10.6000/1929-2279.2014.03.03.7

Keywords:

ABCB1, multidrug resistance, paclitaxel, sildenafil.

Abstract

 The overexpression of ATP-binding cassette (ABC) transporters can produce multidrug resistance (MDR) in cancer cells. Previous in vitro studies from our group reported that sildenafil significantly inhibits the efflux function of the ABCB1/P-glycoprotein transporter in vitro. This investigation examined the effect of sildenafil on the ABCB1 transporter-mediated MDR in vivo. A nude mouse ABCB1 overexpressing-xenograft model was used to examine the effect of sildenafil in vivo. The concentration of paclitaxel in tumors and plasma was analyzed using high performance liquid chromatography (HPLC). Sildenafil attenuated tumor growth synergistically, and this occurred without significant weight loss or other overt phenotypic changes. The action of sildenafil can be attributed to the inhibition of the ABCB1-mediated drug efflux, thereby increasing the concentration of paclitaxel in ABCB1-overexpressing tumors. The potentiation of the pharmacologic action of paclitaxel by sildenafil suggests that it may be useful in treating cancers that overexpress the ABCB1 transporter.

References

Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med 2002; 53: 615-27. http://dx.doi.org/10.1146/annurev.med.53.082901.103929

Bradbury PA, Middleton MR. DNA repair pathways in drug resistance in melanoma. Anticancer Drugs 2004; 15: 421-26. http://dx.doi.org/10.1097/01.cad.0000127665.74096.93

Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. Oncologist 2003; 8: 411-24. http://dx.doi.org/10.1634/theoncologist.8-5-411

Perez-Tomas R. Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr Med Chem 2006; 13: 1859-76. http://dx.doi.org/10.2174/092986706777585077

Tiwari AK, Sodani K, Wang SR, et al. Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol 2009; 78: 153-61. http://dx.doi.org/10.1016/j.bcp.2009.04.002

Tiwari AK, Sodani K, Dai CL, Ashby CR, Jr., Chen ZS, Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol 2011; 12: 570-94. http://dx.doi.org/10.2174/138920111795164048

Hegedus C, Ozvegy-Laczka C, Apati A, et al. Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. Br J Pharmacol 2009; 158: 1153-64. http://dx.doi.org/10.1111/j.1476-5381.2009.00383.x

Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47-52.

Shi Z, Tiwari AK, Shukla S, et al. Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance. Cancer Res 2011; 71: 3029-41. http://dx.doi.org/10.1158/0008-5472.CAN-10-3820

Tiwari AK, Sodani K, Dai CL, et al. Nilotinib potentiates anticancer drug sensitivity in murine ABCB1-, ABCG2-, and ABCC10-multidrug resistance xenograft models. Cancer Lett 2013; 328: 307-17. http://dx.doi.org/10.1016/j.canlet.2012.10.001

Das A, Durrant D, Mitchell C, et al. Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. Proc Natl Acad Sci USA 2010; 107: 18202-207. http://dx.doi.org/10.1073/pnas.1006965107

Warrington JS, Shader RI, von Moltke LL, Greenblatt DJ. In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. Drug Metab Dispos 2000; 28: 392-97.

Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab 2008; 9: 310-22. http://dx.doi.org/10.2174/138920008784220664

Lin F, Hoogendijk L, Buil L, Beijnen JH, van Tellingen O. Sildenafil is not a useful modulator of ABCB1 and ABCG2 mediated drug resistance in vivo. Eur J Cancer 2013; 49: 2059-64. http://dx.doi.org/10.1016/j.ejca.2012.12.028

Downloads

Published

2014-07-29

Issue

Vol. 3 No. 3 (2014)

Section

Articles

How to Cite

Sildenafil Enhances the Anticancer Activity of Paclitaxel in an ABCB1-Mediated Multidrug Resistance Xenograft Mouse Model. (2014). Journal of Cancer Research Updates, 3(3),  169-173. https://doi.org/10.6000/1929-2279.2014.03.03.7

Similar Articles

1-10 of 35

You may also start an advanced similarity search for this article.

Most read articles by the same author(s)