Abstract
Despite the remarkable clinical responses achieved with BCR-ABL tyrosine kinase inhibitors (TKIs) in the treatment of chronic phase-chronic myeloid leukemia (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. It is well known that the mitochondrial metabolic properties of tumor cells are different from those of normal cells, making this as an attractive target for cancer treatment. Previously, we screened a number of antimicrobial drugs with possible mechanisms of action related to mitochondrial metabolism and identified mefloquine as a potential candidate for CML treatment. Mefloquine is a FDA-approved antimalarial drug and has been 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 induces apoptosis of CML cells in a dose-dependent manner (Fig. 1A). 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 (Fig. 2). Mefloquine significantly enhanced anti-proliferative and pro-apoptotic effects of imatinib and dasatinib in CML cell lines as well as BP-CML CD34 cells, suggesting that mefloquine augments the effects of BCR-ABL TKIs (Fig. 1B, 2A and 2B). Mechanistically, we show that mefloquine significantly induces oxidative stress by increasing levels of mitochondrial superoxidase in K562 cells (Fig, 1C). Consistent with this, mefloquine disrupts lysosomal integrity/function in CML cells as measured by LysoTracker labelling (Fig. 1D).
Taken together, we demonstrate that mefloquine is active against BP-CML and enhances the efficacy of BCR-ABL TKIs. Our work also highlights the therapeutic value of targeting oxidative stress and lysosome in the treatment of BP-CML.
Figure 1 Mefloquine induces apoptosis, ROS, and lysosomal dysfunction in CML cells. (A)Mefloquine induces apoptosis of K562, LAMA84 and KU812 cells in a dose-dependent manner. (B) Combination of mefloquine and imatinib or dasatinib induces more much apoptosis than single drug alone. Cells were treated with drugs for 72 h. (C) Mefloquine increases levels of mitochondrial superoxidase in K562 cells. (D) Less Lysotracker staining in mefloquine-treated K562 cells compared to control. Cells were treated with mefloquine at 15 µM for 24 h. Figure 1. Mefloquine induces apoptosis, ROS, and lysosomal dysfunction in CML cells. (A)Mefloquine induces apoptosis of K562, LAMA84 and KU812 cells in a dose-dependent manner. (B) Combination of mefloquine and imatinib or dasatinib induces more much apoptosis than single drug alone. Cells were treated with drugs for 72 h. (C) Mefloquine increases levels of mitochondrial superoxidase in K562 cells. (D) Less Lysotracker staining in mefloquine-treated K562 cells compared to control. Cells were treated with mefloquine at 15 µM for 24 h. Figure 2 Mefloquine effectively targets BP-CML CD34 progenitor cells. Mefloquine induces apoptosis (A) and colony formation (B) of BP-CML CD34 cells and combination of mefloquine and dasatinib is superior in inducing apoptosis and decreasing colony formation. (C) Mefloquine inhibits self-renewal capacity of BP-CML CD34 cells. Figure 2. Mefloquine effectively targets BP-CML CD34 progenitor cells. Mefloquine induces apoptosis (A) and colony formation (B) of BP-CML CD34 cells and combination of mefloquine and dasatinib is superior in inducing apoptosis and decreasing colony formation. (C) Mefloquine inhibits self-renewal capacity of BP-CML CD34 cells.
Disclosures
Hwang: Sanofi: Honoraria, Other: Travel support; Janssen: Honoraria, Other: Travel support; BMS: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support; Roche: Honoraria, Other: Travel support; Pfizer: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria; Chiltern: Honoraria.
Macrophage inflammatory protein-1 alpha receptors are present on cells enriched for CD34 expression from patients with chronic myeloid leukemia
