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PI-103 sensitizes acute myeloid leukemia stem cells to daunorubicin-induced cytotoxicity. | LitMetric

AI Article Synopsis

  • - Acute myeloid leukemia (AML) has poor outcomes with conventional chemotherapy due to leukemia stem cells (LSCs), which are resistant to treatment and contribute to relapse.
  • - The novel molecule PI-103 can inhibit the activated PI3K/Akt/mTOR signaling pathway in LSCs, leading to their apoptosis when used in combination with the chemotherapy drug daunorubicin (DNR).
  • - The combination of PI-103 and DNR significantly induces death in LSCs while sparing healthy hematopoietic stem cells, suggesting a potential less toxic treatment approach for AML that warrants further research.

Article Abstract

To date, acute myeloid leukemia (AML) shows very poor outcome for conventional chemotherapy. Leukemia stem cells (LSCs) are insensitive to conventional chemotherapeutic drugs and play a central role in the pathogenesis of AML. Failure to effectively ablate these cells may lead to AML relapse following chemotherapy. Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constructively activated in LSCs. This pathway can be inhibited by PI-103, a novel synthesized molecule of the pyridofuropyrimidine class, resulting in the apoptosis of LSCs. Therefore, we investigate the influences of PI-103 in combination with daunorubicin (DNR) on the LSCs. Our data indicate that PI-103 synergistically sensitizes LSCs to DNR-induced cytotoxicity. In addition, the PI-103/DNR co-treatment can induce significant apoptosis in LSCs, but sparing hematopoietic stem cells. The synergistic effect and the LSCs-specific apoptosis mechanism may be associated with the inhibition of PI3K/Akt/mTOR signaling pathway. Our results suggest that PI-103 in combination with DNR may be a potent and less toxic therapy for targeting LSCs and deserve further preclinical and clinical studies in the treatment of AML.

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Source
http://dx.doi.org/10.1007/s12032-012-0395-5DOI Listing

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