HDAC I/IIb selective inhibitor Purinostat Mesylate combined with GLS1 inhibition effectively eliminates CML stem cells

Purinostat Mesylate(PM)is a novel highly selective and active HDAC I/IIb inhibitor,and the injectable formulation of PM(PMF)based on the compound prescription containing cyclodextrin completely can overcome PM’s poor solubility and improves its stability and pharmacokinetic properties.Here,we showed that PM effectively repressed the survival of Ph+leukemia cells and CD34+leukemia cells from CML patients in vitro.In vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I)induced CML progression by restraining leukemia stem cells(LSCs),which are insensitive to chemotherapy and responsible for CML relapse.Mechanism studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc,β-Catenin,E2f,Ezh2,Alox5,and mTOR,as well as interrupted some critical biologic processes.Additionally,PMF increased glutamate metabolism in LSCs by increasing GLS1.The combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and self-renewal.Overall,our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis,which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients.

β-Elemene-loaded polymeric micelles intensify anti-carcinoma efficacy and alleviate side effects

β-Elemene is a volatile oil used for the treatment of cancer,but poor solubility,low bioavailability,and various adverse reactions limit its application.For amelio rating risks of the venous toxicity ofβ-elemene,intravenously injectable micelle ofβ-elemene was prepared using the thin-film hydration method.The results pointed out the micelles were uniformly spherical with about 20.96±0.1966 nm in average diameter and exhibited high entrapment efficiency(99.02%±0.88%).As revealed by drug release studies in vitro,β-elemene micelles had sustained drug release.Compared with freeβ-elemene,the micelles increased the drug cellular uptake and enhanced the anti-tumor effect in vitro through retarding cell cycle and inducing apoptosis.Meanwhile,the elevated se rum stability o fβ-elemene micelles implied less drug leakage and reduced toxicity.The wound healing and tube formation assay in vitro demonstrated the anti-metastasis and anti-angiogenesis effects ofβ-elemene micelles.Moreover,the pharmacokinetics study showed the AUC and T1/2 ofβ-elemene in micelle group were 1.79 and 1.62 times of that in free fi-elemene group,suggesting the circulation time ofβ-elemene in the blood had been prolonged.In addition,β-elemene micelles showed a favorable antitumor response compared with theβ-elemene solution on C26 colon cance r-bearing mice model.Local irritation study investigated in rabbits indicated that theβ-elemene micelles strikingly mitigated the irritation to the injection sites compared with freeβ-elemene.These results proved that the micelle could be a good candidate as an auspicious drug delivery system ofβ-elemene for the prospective clinical treatment of carcinoma.