Repurposing Antimalarial Drug Mefloquine for Cancer Treatment

Abstract

Mefloquine (MQ) is a quinoline class of drugs that has been in clinical use for the last four decades for the prophylaxis and treatment of malaria. Several recent literature studies on MQ illustrate that this drug exhibits good to excellent cytotoxicity and cell proliferation inhibition against several cancer cells. MQ also exhibits good in vivo tumor growth inhibition as a single agent and effectively synergizes with primary cancer chemotherapeutics in arresting tumor growth. Mechanism of action studies indicate that MQ has pleiotropic effects on cancer cells that include inhibition of autophagy, lysosomal disruption, inhibition of various signaling pathways, and inhibition of Pgp pumps. Based on the in vitro and in vivo anticancer efficacy data, MQ has excellent potential to succeed as an adjuvant therapy as well as a primary agent in combination with chemotherapeutics for many solid and hematological malignancies. MQs ready and inexpensive availability and long-standing record of clinical use qualify this drug for repurposing for anticancer applications.

Mefloquine induces ER stress and apoptosis in BRAFi‐resistant A375‐BRAFV600E/NRASQ61K malignant melanoma cells targeting intracranial tumors in a bioluminescent murine model

“…24 Among various aminoquinoline-antimalarials, cancer celldirected cytotoxicity of MQ is well documented, involving numerous tentative molecular mechanisms, including autophagic-lysosomal blockade, inhibition of P-glycoprotein-dependent drug efflux, NFκB pathway attenuation through IKK inactivation, and induction of redox dysregulation. [46][47][48][49] Here we demonstrate for the first time that MQ induces cell death in cultured malignant melanoma cells displaying apoptogenic activity observable even in BRAFi-resistant BRAF V600E /NRAS Q61K A375 melanoma cells (Figures 1 and 4), an effect associated with rapid induction of proteotoxic and oxidative stress response gene expression (Figure 2).…”

“…Repurposing of clinical antimalarials has shown promise for cancer‐directed molecular intervention, and inhibitory modulation of autophagic‐lysosomal function has been substantiated as a major molecular mechanism of action underlying cancer cell‐directed activity of antimalarials 24 . Among various aminoquinoline‐antimalarials, cancer cell‐directed cytotoxicity of MQ is well documented, involving numerous tentative molecular mechanisms, including autophagic‐lysosomal blockade, inhibition of P‐glycoprotein‐dependent drug efflux, NFκB pathway attenuation through IKK inactivation, and induction of redox dysregulation 46–49 …”

In silico exploration of anti-prostate cancer compounds from differential expressed genes

“…Mefloquine is an antimalarial compound with anticancer potential [ 60 ]. A previous experimental study has shown that mefloquine at 20 µM selectively and completely abolished the cell proliferation of two human PCa cell lines DU145 and PC3, by hyperpolarization of mitochondrial membrane potential and increased production of ROS resulting in rapid cancer cell death through inhibition of Akt phosphorylation and activated JNK, ERK and AMPK signaling [ 60 – 62 ].…”

Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach

“…Loss of cell viability at compound 5 (Mefloquine Hydrochloride, MH) concentrations around sevenfold lower than those observed in the aggregate refolding assays, most likely indicates that the effect of this drug could be due to a mechanism different from chaperone inhibition. Indeed, it has been reported that similar MH concentrations exert antiproliferative effects through an increased lysosomal biogenesis and activation, followed by oxidative stress, lysosomal lipid damage and functional impairment [80].…”