Effects of Mefloquine on the Release of Marker Enzymes from the Rat Liver Crude Lysosomal Fraction

Go, Mei‐Lin; Lee, How Sung

doi:10.1254/jjp.53.195

Cited by 4 publications

(1 citation statement)

References 16 publications

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“…Mefloquine produces a rapid and biphasic response in lysosomal biogenesis prior to inducing lysosomal lipid damage and dysfunction of CML cells in our experiments. It reflects a common feature of lysosomal response to mefloquine in mammalian cells and parasites [33], [34]. These responses are consistent with the effects of lysosomotropic agents that evoke an initial compensatory lysosomal biogenic response but with the ultimate consequence of lysosomal dysfunction [22].…”

Section: Discussionsupporting

confidence: 71%

Lysosome Inhibition by Mefloquine Preferentially Enhances the Cytotoxic Effects of Tyrosine Kinase Inhibitors in Blast Phase Chronic Myeloid Leukemia

Than

Sng

et al. 2019

Translational Oncology

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Despite the efficacy of BCR-ABL tyrosine kinase inhibitors (TKIs) in chronic phase-chronic myeloid leukemia, the management of blast phase-chronic myeloid leukemia (BP-CML) remains a challenge. Therefore, there is an urgent need to identify alternative agents that act synergistically with BCR-ABL TKIs in BP-CML. Our results show that the anti-malarial agent, mefloquine augments the efficacy of TKIs in CML cell lines and primary CML cells in vitro, including those with the T315I mutation. This effect is selective as mefloquine is more effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34 + cells derived from TKI-resistant BP-CML patients than normal cord blood (CB) CD34 + stem/progenitor cells. Notably, the combination of mefloquine and TKIs at sublethal concentrations leads to synergistic effects in CML CD34 + cells, while sparing normal CB CD34 + cells. We further demonstrate that the initial action of mefloquine in CML cells is to increase lysosomal biogenesis and activation, followed by oxidative stress, lysosomal lipid damage and functional impairment. Taken together, our work elucidates that mefloquine selectively augments the effects of TKIs in CML stem/progenitor cells by inducing lysosomal dysfunction.

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Section: Discussionsupporting

confidence: 71%

Lysosome Inhibition by Mefloquine Preferentially Enhances the Cytotoxic Effects of Tyrosine Kinase Inhibitors in Blast Phase Chronic Myeloid Leukemia

Than

Sng

et al. 2019

Translational Oncology

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Chloroquine, a novel inhibitor of amino acid transport by rat renal brush border membrane vesicles

Chesney

Budreau

1995

Amino Acids

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Chloroquine is an antimalarial and antirheumatic lysosomotropic drug which inhibits taurine uptake into and increases efflux from cultured human lymphoblastoid cells. It inhibits taurine uptake by rat lung slices and affects the uptake and release of cystine from cystinotic fibroblasts. Speculations on its mode of action include a proton gradient effect, a non-specific alteration in membrane integrity, and membrane stabilization. In this study, the effect of chloroquine on the uptake of several amino acids by rat renal brush border membrane vesicles (BBMV) was examined. Chloroquine significantly inhibited the secondary active, NaCl-dependent component of 10µM taurine uptake at all concentrations tested, but did not change equilibrium values. Analysis of these data indicated that the inhibition was non-competitive. Taurine uptake was reduced at all osmolarities tested, but inhibition was greatest at the lowest osmolarity. Taurine efflux was not affected by chloroquine, nor was the NaCl-independent diffusional component of taurine transport. Chloroquine (1 mM) inhibited uptake of the imino acids L-proline and glycine, and the dibasic amino acid L-lysine. It inhibited the uptake of D-glucose, but not the neutralα-amino acids L-alanine or L-methionine. Uptake of the dicarboxylic amino acids, L-glutamic acid and L-aspartic acid, was slightly enhanced. With regard to amino acid uptake by BBMV, these findings may support some of the currently proposed mechanisms of the action of chloroquine but further studies are indicated to determine why it affects the initial rate of active amino acid transport.

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Hydrolysis of retinyl esters in rat liver. Description of a lysosomal activity

Mercier¹,

Forget²,

Grolier³

et al. 1994

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

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Effects of Mefloquine on the Release of Marker Enzymes from the Rat Liver Crude Lysosomal Fraction

Abstract: Abstract-The

Cited by 4 publications

References 16 publications

Lysosome Inhibition by Mefloquine Preferentially Enhances the Cytotoxic Effects of Tyrosine Kinase Inhibitors in Blast Phase Chronic Myeloid Leukemia

Lysosome Inhibition by Mefloquine Preferentially Enhances the Cytotoxic Effects of Tyrosine Kinase Inhibitors in Blast Phase Chronic Myeloid Leukemia

Chloroquine, a novel inhibitor of amino acid transport by rat renal brush border membrane vesicles

Hydrolysis of retinyl esters in rat liver. Description of a lysosomal activity

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