Potent anti-proliferative effect of fatty-acid derivative AIC-47 on leukemic mice harboring BCR-ABL mutation.

Potent anti-proliferative effect of fatty-acid derivative AIC-47 on leukemic mice harboring BCR-ABL mutation.

Cancer Sci. 2018 Dec 12;:

Authors: Shinohara H, Sugito N, Kuranaga Y, Heishima K, Minami Y, Naoe T, Akao Y

Abstract
Therapy based on targeted inhibition of BCR-ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)-positive leukemia and tyrosine kinase inhibitors (TKIs) have become the standard therapy. However, some patients acquire resistance to TKIs that is frequently associated with point mutations in the BCR-ABL. We previously reported that a medium-chain fatty-acid derivative AIC-47 induced transcriptional suppression of BCR-ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph-positive leukemia cells. Herein we showed that AIC-47 had anti-leukemic effects in either wild type (WT)- or mutated-BCR-ABL-harboring cells. AIC-47 suppressed transcription of BCR-ABL gene regardless of the mutation through the down-regulation of transcriptional activator, c-Myc. The reprogramming of metabolic pathway has been reported to be associated with resistance to anti-cancer drugs; however, we found that a point mutation of BCR-ABL was independent of the profile of PKM isoform expression. Even in T315I-mutated cells, AIC-47 induced switching the expression profile of pyruvate kinase muscle (PKM) isoforms from PKM2 to PKM1, suggesting that AIC-47 perturbed the Warburg effect. In a leukemic mouse model, AIC-47 extremely suppressed the increase in BCR-ABL mRNA level and improved hepatosplenomegaly regardless of the BCR-ABL mutation. Notably, the improvement of splenomegaly by AIC-47 was remarkable and might be equal to greater than TKIs. These findings suggest that AIC-47 might be a promising agent for overcoming the resistance of Ph-positive leukemia to therapy. This article is protected by copyright. All rights reserved.

PMID: 30548479 [PubMed - as supplied by publisher]

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