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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Number of pages1
JournalJournal of translational medicine
Volume17
Issue number1
DOIs
StatePublished - May 20 2019

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Acute Myeloid Leukemia
Cells
Myeloid Cells
Cell Line
Blood Component Removal
Therapeutics
Apoptosis
Diterpenes
Tripterygium
Epoxy Compounds
Prodrugs
Cell growth
Cell death
Caspases
Stem cells
Luciferases
Safety
Imaging systems
Neoplasms
Maximum Tolerated Dose

Keywords

  • Acute myeloid leukemia
  • AML
  • c-Myc
  • Minnelide
  • Triptolide

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Pre-clinical evaluation of Minnelide as a therapy for acute myeloid leukemia. / Giri, Bhuwan; Gupta, Vineet K.; Yaffe, Brianna; Modi, Shrey; Roy, Pooja; Sethi, Vrishketan; Lavania, Shweta P.; Vickers, Selwyn M.; Dudeja, Vikas; Banerjee, Sulagna; Watts, Justin; Saluja, Ashok.

In: Journal of translational medicine, Vol. 17, No. 1, 20.05.2019.

Research output: Contribution to journalArticle

Giri, Bhuwan ; Gupta, Vineet K. ; Yaffe, Brianna ; Modi, Shrey ; Roy, Pooja ; Sethi, Vrishketan ; Lavania, Shweta P. ; Vickers, Selwyn M. ; Dudeja, Vikas ; Banerjee, Sulagna ; Watts, Justin ; Saluja, Ashok. / Pre-clinical evaluation of Minnelide as a therapy for acute myeloid leukemia. In: Journal of translational medicine. 2019 ; Vol. 17, No. 1.
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AU - Giri, Bhuwan

AU - Gupta, Vineet K.

AU - Yaffe, Brianna

AU - Modi, Shrey

AU - Roy, Pooja

AU - Sethi, Vrishketan

AU - Lavania, Shweta P.

AU - Vickers, Selwyn M.

AU - Dudeja, Vikas

AU - Banerjee, Sulagna

AU - Watts, Justin

AU - Saluja, Ashok

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AB - 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.

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