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D. Wu et al.
Previous studies have shown that O-linked N-acetylglu- cosamine transferase (OGT) is directly involved in the reg- ulation of MYC expression.31, 32 As expected, our results fur- ther showed that isobavachalcone treatment led to a signif- icant reduction of OGT (Online Supplementary Figure S8B). Taken together, these findings indicate that the inhibition of DHODH by isobavachalcone induces MYC degrada- tion-dependent differentiation of AML cells.
isobavachalcone exhibits antitumor efficacy by inhibiting dihydroorotate dehydrogenase activity in vivo
Figure 5A shows that isobavachalcone significantly suppressed tumor growth (37.81 ± 4.32% and 78.91 ± 9.73%, 15 and 30 mg/kg isobavachalcone, respectively),
compared with the control group, in a subcutaneous HL60 xenograft mouse model. Similarly, the weight of tumors in the groups of animals treated with isobavachalcone was significantly reduced (Figure 5B) by 37.65 ± 3.74% and 74.41 ± 8.47%, respectively. No obvi- ous body weight loss or deaths were observed in any of the groups of mice (Figure 5C), suggesting that isobavachalcone has a low toxicity in vivo. Hematoxylin and eosin staining analysis further supports the potent tumor suppression exerted by isobavachalcone on the HL60 xenograft model (Figure 5D) without significant damage to the main organs of the mice treated with this compound (Figure 5E). We then examined the expression level and activity of DHODH protein in vivo. Western
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Figure 6. The combination of isobavachalcone and adriamycin shows synergistic antileukemic effects in vitro and in vivo. (A-D) Synergistic effects of the isobavachalcone and adriamycin combination on AML cells. AML cell lines (HL60, THP1, U937 and MOLM-13) were treated with several increasing concentrations of isobavachalcone and adriamycin alone or in combination for 48 h. The combination index (CI) calculation was performed using CalcuSyn software (Version 2.1; Biosoft). Drug combinations with a CI<1 are considered to be synergistic. (E) Synergistic effects of isobavachalcone and adriamycin combination therapy in an intra- venous HL60 leukemia model. Mice with established tumors (4 per group) were divided into four groups and treated with vehicle, isobavachalcone, adriamycin or a combination of isobavachalcone and adriamycin. The P value was determined using the log-rank test, P=0.0003 for the survival analysis (E). (F) Leukemia cells iso- lated from the isobavachalcone-treated group exhibit morphological features of differentiation. ADR: adriamycin; IBC: isobavachalocone.
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haematologica | 2018; 103(9)