@article{f36fcc68f1ce4d0bbc8039c29a0cc1f9,
title = "Simvastatin enhances the efficacy of nilotinib in chronic myeloid leukaemia by post-translational modification and drug transporter modulation",
abstract = "The resistance of chronic myeloid leukaemia (CML) to tyrosine kinase inhibitors (TKIs) remains a significant clinical problem. Targeting alternative pathways, such as protein prenylation, is known to be effective in overcoming resistance. Simvastatin inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (a key enzyme in isoprenoid-regulation), thereby inhibiting prenylation. We demonstrate that simvastatin alone effectively inhibits proliferation in a panel of TKI-resistant CML cell lines, regardless of mechanism of resistance. We further show that the combination of nilotinib and simvastatin synergistically kills CML cells via an increase in apoptosis and decrease in prosurvival proteins and cellular proliferation. Mechanistically, simvastatin inhibits protein prenylation as shown by increased levels of unprenylated Ras and rescue experiments with mevalonate resulted in abrogation of synergism. The combination also leads to an increase in the intracellular uptake and retention of radio-labelled nilotinib, which further enhances the inhibition of Bcr-Abl kinase activity. In primary CML samples, this combination inhibits clonogenicity in both imatinib-naive and resistant cells. Such combinatorial effects provide the basis for utilising these Food and Drug Administration-approved drugs as a potential clinical approach in overcoming resistance and improving CML treatment.",
keywords = "chronic myeloid leukaemia, drug transporters, nilotinib, prenylation, simvastatin",
author = "Kartini Asari and Sun, {Wen Tian} and Kok, {Ze Hui} and Lam, {Yi Hui} and Ng, {Bee Ling} and Verity Saunders and White, {Deborah L.} and Charles Chuah and Wei Xiang",
note = "Funding Information: C.C. has received research funding from Bristol-Myers Squibb and honoraria from Bristol-Myers Squibb, Novartis Oncology, Korea Otsuka Pharmaceuticals and Chiltern International. D.L.W. has received honoraria and research funding from Bristol-Myers Squibb and Novartis Oncology. For the remaining authors, there are no conflicts of interest. Funding Information: This work was supported by the National Research Foundation Singapore under Clinician Scientist Awards, NMRC/CSA/017/2010 (C.C.) and administered by the Singapore Ministry of Health{\textquoteright}s National Medical Research Council (NMRC);by the Agency for Science,Technology, and Research (A*STAR) Biomedical Research Council Translational Clinical Research Partnership Grant, BMRC/13/1/96/681 (C.C.); by the Duke-National University of Singapore Signature Research Program funded by the A*STAR and the Ministry of Health, Singapore (C.C.); by the Academia Medical Research Grant AM/TP020/2018(SRDUKAMR1820) (X.W.); NMRC Centre Grant Programme-Targeted Therapy for Blood Cancer, NMRC/CG/C012A/2017 (C.C.); NMRC Clinician Scientist/Clinician Investigator Salary Support Programme, NMRC/CISSP/2015/018a (C.C.); and by NHMRC Project Grant 2009 and 2012 and Cancer Council of SA 2012 (D.L.W.). Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved.",
year = "2021",
month = jun,
day = "1",
doi = "10.1097/CAD.0000000000001028",
language = "English",
volume = "32",
pages = "526--536",
journal = "Anti-Cancer Drugs",
issn = "0959-4973",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "5",
}