Synergistic Effect of Farnesyl Transferase Inhibitor Lonafarnib Combined with Chemotherapeutic Agents Against the Growth of Hepatocellular Carcinoma Cells

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Dec 30

PMID 29285232

Citations 6

Authors

Jialiang Wang

Yifan Lian

Yurong Gu

Hongbo Wang

Lin Gu

Yanlin Huang

Liang Zhou

Yuehua Huang

Affiliations

Soon will be listed here.

Abstract

Hepatocellular carcinoma (HCC) is a common and deadly cancer worldwide and is often refractory to chemotherapy due to the development of multidrug resistance. Lonafarnib is an orally active and potent non-peptidomimetic inhibitor of farnesyl transferase. Here, using HCC cell models, we demonstrated that lonafarnib inhibited tumor proliferation and reduced the activity of mitogen-activated protein kinases pathways. In addition, lonafarnib caused G1 to S phase arrest through the downregulation of Cyclin D1, CDK6 and SKP2, while it induced cellular apoptosis by promoting the cleavage and activation of Caspase-3 and PARP. When combined with doxorubicin and sorafenib, lonafarnib was able to increase the sensitivity of HCC cells to chemotherapy. Furthermore, we also constructed ABCB1-overexpressing HCC cells and found that lonafarnib decreased chemoresistance by inhibiting ABCB1-mediated drug efflux activity. These results suggest that lonafarnib may be a promising synergistic agent for improving the treatment of drug-resistant HCC.

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References

Bruix J, Gores G, Mazzaferro V . Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014; 63(5):844-55. PMC: 4337888. DOI: 10.1136/gutjnl-2013-306627. View

Belghiti J, Fuks D . Liver resection and transplantation in hepatocellular carcinoma. Liver Cancer. 2013; 1(2):71-82. PMC: 3747544. DOI: 10.1159/000342403. View

Forner A, Llovet J, Bruix J . Hepatocellular carcinoma. Lancet. 2012; 379(9822):1245-55. DOI: 10.1016/S0140-6736(11)61347-0. View

Wong N, Morse M . Lonafarnib for cancer and progeria. Expert Opin Investig Drugs. 2012; 21(7):1043-55. DOI: 10.1517/13543784.2012.688950. View

Zhu R, Seto W, Lai C, Yuen M . Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region. Gut Liver. 2016; 10(3):332-9. PMC: 4849684. DOI: 10.5009/gnl15257. View

Wang Z, Zhang G, Wu J, Jia M . Adjuvant therapy for hepatocellular carcinoma: current situation and prospect. Drug Discov Ther. 2013; 7(4):137-43. View

Tanaka M, Katayama F, Kato H, Tanaka H, Wang J, Qiao Y . Hepatitis B and C virus infection and hepatocellular carcinoma in China: a review of epidemiology and control measures. J Epidemiol. 2011; 21(6):401-16. PMC: 3899457. DOI: 10.2188/jea.je20100190. View

Bruix J, Llovet J . Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 2002; 35(3):519-24. DOI: 10.1053/jhep.2002.32089. View

Te Boekhorst P, van Kapel J, Schoester M, Sonneveld P . Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive analogue SDZ PSC 833 in Chinese hamster ovary cells expressing the mdr1 phenotype. Cancer Chemother Pharmacol. 1992; 30(3):238-42. DOI: 10.1007/BF00686322. View

10.

Chow L, Eckhardt S, OBryant C, Schultz M, Morrow M, Grolnic S . A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2007; 62(4):631-46. PMC: 2813768. DOI: 10.1007/s00280-007-0646-x. View

11.

Kim J, Chung J, Park I, Kim B, Yoo N, Choi J . Combined use of tamoxifen, cyclosporin A, and verapamil for modulating multidrug resistance in human hepatocellular carcinoma cell lines. Yonsei Med J. 1993; 34(1):35-44. DOI: 10.3349/ymj.1993.34.1.35. View

12.

Schlageter M, Terracciano L, DAngelo S, Sorrentino P . Histopathology of hepatocellular carcinoma. World J Gastroenterol. 2014; 20(43):15955-64. PMC: 4239483. DOI: 10.3748/wjg.v20.i43.15955. View

13.

Moriguchi M, Umemura A, Itoh Y . Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma. Clin J Gastroenterol. 2016; 9(4):184-90. DOI: 10.1007/s12328-016-0670-7. View

14.

Gottesman M, Pastan I . Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993; 62:385-427. DOI: 10.1146/annurev.bi.62.070193.002125. View

15.

Lai C, Ratziu V, Yuen M, Poynard T . Viral hepatitis B. Lancet. 2003; 362(9401):2089-94. DOI: 10.1016/S0140-6736(03)15108-2. View

16.

Basso A, Mirza A, Liu G, Long B, Bishop W, Kirschmeier P . The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J Biol Chem. 2005; 280(35):31101-8. DOI: 10.1074/jbc.M503763200. View

17.

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

18.

Wu Q, Yang Z, Nie Y, Shi Y, Fan D . Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett. 2014; 347(2):159-66. DOI: 10.1016/j.canlet.2014.03.013. View

19.

Zhong Y, Liu B, Deng M, Xu R . Adjuvant systemic drug therapy and recurrence of hepatocellular carcinoma following curative resection. Drug Discov Ther. 2013; 7(4):164-6. View

20.

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View