Abstract
BackgroundThere 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.MethodsCell 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).ResultsIn 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.ConclusionOur 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.
Highlights
There is an urgent need for novel and effective treatment options for acute myeloid leukemia (AML)
In the current study we show that Minnelide is effective against AML at a very low dose both in vivo and in vitro
The mice were irradiated with 250 cGy, to facilitate engraftment, and 2 × 106 THP-1 AML cells with Luciferase reporter gene were injected via tail vein
Summary
There is an urgent need for novel and effective treatment options for acute myeloid leukemia (AML). The general treatment guidelines for AML have not changed in the last 40 years [3] and consists of high dose infusion of cytarabine in combination with an anthracycline (doxorubicin or daunorubicin). As such, this aggressive chemotherapy regimen is poorly tolerated and comes with significant side effects [4]. AML typically affects the elderly [7] which tolerate the aggressive chemotherapy regimen poorly. Novel therapy that is both well tolerated and effective is the need of the hour
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