Pre-clinical evaluation of Minnelide as a therapy for acute myeloid leukemia.

Abstract

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.

• Authors: Bhuwan Giri, Vineet K Gupta, Brianna Yaffe, Shrey Modi, Pooja Roy, Vrishketan Sethi, Shweta P Lavania, Selwyn M Vickers, Vikas Dudeja, Sulagna Banerjee, Justin Watts, Ashok Saluja
• Journal: Journal of translational medicine (J Transl Med) Vol. 17 Issue 1 Pg. 163 (05 20 2019) ISSN: 1479-5876 [Electronic] England
• PMID: 31109340 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Diterpenes
• Epoxy Compounds
• Organophosphates
• Phenanthrenes
• Proto-Oncogene Proteins c-myc
• triptolide
• 14-O-phosphonooxymethyltriptolide disodium salt

Topics

• Animals
• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Diterpenes (pharmacology, therapeutic use)
• Down-Regulation (drug effects)
• Drug Evaluation, Preclinical
• Epoxy Compounds
• Humans
• Leukemia, Myeloid, Acute (drug therapy)
• Mice
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Organophosphates (pharmacology, therapeutic use)
• Phenanthrenes (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-myc (metabolism)
• Tumor Burden (drug effects)
• Tumor Stem Cell Assay