Background There is an urgent need for novel and effective treatment options for acute myeloid leukemia (AML). Triptolide, a diterpenoid tri-epoxide compound isolated from the herb Tripterygium wilfordii and its water-soluble pro-drug-Minnelide have shown promising anti-cancer activity. A recent clinical trial for patients with solid tumors confirmed the safety and efficacy at biologically equivalent doses of 0.2 mg/kg/day and lower. Methods Cell viability of multiple AML cell lines as well as patient apheresis samples were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) based assay. Apoptosis was evaluated by estimating the amount of cleaved caspase. AML cell line (THP1-Luc) was implanted in immunocompromised mice and treated with indicated doses of Minnelide. Leukemic burden before and after treatment was evaluated by imaging in an In Vivo Imaging System (IVIS). Results In the current study, we show that Minnelide, at doses below maximum tolerated dose (MTD) demonstrates leukemic clearance of both primary AML blasts and luciferase expressing THP-1 cells in mice. In vitro, multiple primary AML apheresis samples and AML cell lines (THP-1, KG1, Kasumi-1, HL-60) were sensitive to triptolide mediated cell death and apoptosis in low doses. Treatment with triptolide led to a significant decrease in the colony forming ability of AML cell lines as well as in the expression of stem cell markers. Additionally, it resulted in the cell cycle arrest in the G1/S phase with significant downregulation of c-Myc, a major transcriptional regulator mediating cancer cell growth and stemness. Conclusion Our results suggest that Minnelide, with confirmed safety and activity in the clinic, exerts a potent anti-leukemic effect in multiple models of AML at doses easily achievable in patients. Electronic supplementary material The online version of this article (10.1186/s12967-019-1901-8) contains supplementary material, which is available to authorized users.

Decellularized nerve hydrogels (dNHs) containing bioactive molecules are promising biomaterials for peripheral nerve injury (PNI) treatment and have been extensively applied in clinical and preclinical practice. However, most previous research projects studied their influences on nerve-related cellular behaviors in two dimensions (2D) without taking hydrogel biomechanics into consideration. The molecular mechanisms underlying the beneficial microenvironment provided by dNHs also remain unclear. In this study, dNHs from rat sciatic nerves were prepared, and their effects on Schwann cell (SC) and dorsal root ganglion (DRG) neurite behaviors were evaluated and compared to commercial rat tail type I collagen (Col) hydrogels in three-dimensional (3D) environments. We found that dNHs could promote SC proliferation and neurite outgrowth, and both the hydrogel mechanics and components contributed to the dNH functionalization. Through proteomics analysis, we found that laminin (LAM) and type V collagen (COLV) exclusively and abundantly existed in dNHs. By adding exogenous LAM and COLV into Col hydrogels, we demonstrated that they regulated SC gene expression and that LAM could promote SC spreading and neurite outgrowth, while COLV improved SC proliferation. Lastly, dNHs were fabricated into paper-like, aligned nerve scaffolds through unidirectional freezing to expand the dNH applications in PNI treatment.

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