プロバイオティクス由来Heptelidic acidは小児B細胞性急性白血病に対して治療効果を発揮する

<p>Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is known to be sensitive to chemotherapy. However, 15-20% of patients experience relapse, and survival rates after relapse can drop to 5-10%. We isolated heptelidic acid (HA) from the probiotic Aspergillus oryzae and demonstrated HA exerted antitumor functions against several cancers. In this study, we assessed the antitumor effects of HA in B-ALL. HA exhibited cytotoxicity in two B-ALL cell lines and three pediatric B-ALL patient samples, while sparing CD34+ hematopoietic stem cells (HSCs). GAPDH activity was measured, as HA can bind to GAPDH. GAPDH activity of HSCs was lower than B-ALL cells. The cytotoxic effect of HA was associated with the reduction of GAPDH activity. Oral daily administration of HA prolonged the survival of the B-ALL patient derived xenograft (PDX) mice. HA demonstrated synergistic effects when combined with chemotherapeutics, especially vincristin (VCR). The combination therapy of HA and VCR resulted in improved survival outcomes in the B-ALL PDX model compared to single-agent treatments. HA treatment caused G2/M arrest, and this was accompanied by increased cleavage of PARP. Moreover, the cytotoxicity of HA was attenuated by RIPK1 inhibition. In conclusion, HA is cytotoxic in B-ALL cells by disrupting glycolysis through the inhibition of GAPDH. The therapeutic efficacy of HA is enhanced when combined with chemotherapeutic agents. The underlying mechanisms of HA involve the induction of RIPK-1 mediated programmed cell death. This is the first study to demonstrate HA as a novel therapeutic agent for B-ALL.</p>