Abstract 1050: Mefloquine enhances the cytotoxic effects of tyrosine kinase inhibitors in blast phase chronic myeloid leukaemia by lysosome membrane disruption
Authors: Xiang Wei , Lam Yi Hui , Sng Colin , Cheong May Anne , Than Hein , Hwang William YK , Chuah Charles 
Published: July 2017

Abstract
Despite the remarkable clinical responses achieved with BCR-ABL tyrosine kinase inhibitors (TKIs) in the treatment of chronic phase-chronic myeloid leukaemia (CML), these TKIs have been less effective as single agents in blast phase (BP) CML. Identification of new therapeutic strategies is needed for the better clinical management of BP-CML. Given the known pharmacokinetics and toxicity profile, drug repurposing represents an alternative therapeutic strategy for CML. Mefloquine is a FDA-approved antimalarial drug that has been recently reported to have anti-cancer activities. In this work, we investigated the effect of mefloquine and its underlying mechanisms in CML.
We show that mefloquine inhibits proliferation and induces apoptosis of CML cells in a dose-dependent manner. In addition, mefloquine is also effective in targeting BP-CML CD34+ progenitor cells. It induces apoptosis, inhibits colony formation and self-renewal capacity of CD34+ cells derived from a TKI-resistant BP-CML patient. Mefloquine significantly enhanced anti-proliferative and pro-apoptotic effects of imatinib and dasatinib in CML cell lines (eg, K562, LAMA84 and KU812) as well as BP-CML CD34+ cells, suggesting that mefloquine augments the effects of BCR-ABL TKIs.
Mechanistically, mefloquine increases lysosome biogenesis in various CML cell lines. The action of mefloquine on lysosome is further confirmed by our observation that the lysosomal vacuolar ATPase bafilomycin A1 rescues mefloquine-induced CML cell death. Mefloquine also induces oxidative stress in CML cells as shown by the increased mitochondrial superoxide levels. Importantly, α-tocopherol (known to inhibit lysosomal lipid-mediated ROS production) but not N-acetyl-L-cysteine (NAC, known to inhibit thiol redox-mediated ROS production) protects against mefloquine-mediated cell death, suggesting that oxidative stress induced by mefloquine in CML cells is lysosome-mediated. It is known that the length of isoprenoid side chain of α-tocopherol is important for the stabilization of biological membranes. Interestingly, α-tocopherol analog Trolox, which differs from α-tocopherol by decreasing isoprenoid side chain fails to rescue mefloquine-induced cell death, suggesting that mefloquine may destabilize lysosome membrane in CML cells. In addition, we show that mefloquine decreases phosphorylation of S6 and increases LC3B II levels, suggesting that mTOR inhibition and autophagy induction might be involved in the action of mefloquine in CML cells.
Taken together, our work suggests that mefloquine has a potential to be repurposed for CML treatment, given its efficacy as a single agent and synergism as combination with BCR-ABL TKIs in CML primary progenitors and cell lines. Our work also highlights the therapeutic value of targeting the lysosome in the treatment of CML.
Citation Format: Wei Xiang, Yi Hui Lam, Colin Sng, May Anne Cheong, Hein Than, William YK Hwang, Charles Chuah. Mefloquine enhances the cytotoxic effects of tyrosine kinase inhibitors in blast phase chronic myeloid leukaemia by lysosome membrane disruption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1050. doi:10.1158/1538-7445.AM2017-1050