Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro

Katie H. Hurrish; Yongwei Su; Shraddha Patel; Cassandra L. Ramage; Jianlei Zhao; Brianna R. Temby; Jenna L. Carter; Holly Edwards; Steven A. Buck; Sandra E. Wiley; Maik Hüttemann; Lisa Polin; Juiwanna Kushner; Sijana H. Dzinic; Kathryn White; Xun Bao; Jing Li; Jay Yang; Julie Boerner; Zhanjun Hou; Gheath Al-Atrash; Sergej N. Konoplev; Jonathan Busquets; Stefano Tiziani; Larry H. Matherly; Jeffrey W. Taub; Marina Konopleva; Yubin Ge; Natalia Baran

doi:10.1016/j.bcp.2023.115981

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro

Katie H. Hurrish, Yongwei Su, Shraddha Patel, Cassandra L. Ramage, Jianlei Zhao, Brianna R. Temby, Jenna L. Carter, Holly Edwards, Steven A. Buck, Sandra E. Wiley, Maik Hüttemann, Lisa Polin, Juiwanna Kushner, Sijana H. Dzinic, Kathryn White, Xun Bao, Jing Li, Jay Yang, Julie Boerner, Zhanjun HouGheath Al-Atrash, Sergej N. Konoplev, Jonathan Busquets, Stefano Tiziani, Larry H. Matherly, Jeffrey W. Taub, Marina Konopleva, Yubin Ge, Natalia Baran

Research output: Contribution to journal › Article › peer-review

Abstract

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

Original language	English (US)
Article number	115981
Journal	Biochemical Pharmacology
Volume	220
DOIs	https://doi.org/10.1016/j.bcp.2023.115981
State	Published - Feb 2024

Keywords

Acute myeloid leukemia
ME-344
Oxidative phosphorylation
Purine biosynthesis
Venetoclax

ASJC Scopus subject areas

Biochemistry
Pharmacology

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10.1016/j.bcp.2023.115981

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Hurrish, K. H., Su, Y., Patel, S., Ramage, C. L., Zhao, J., Temby, B. R., Carter, J. L., Edwards, H., Buck, S. A., Wiley, S. E., Hüttemann, M., Polin, L., Kushner, J., Dzinic, S. H., White, K., Bao, X., Li, J., Yang, J., Boerner, J., ... Baran, N. (2024). Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro. Biochemical Pharmacology, 220, Article 115981. https://doi.org/10.1016/j.bcp.2023.115981

Hurrish, KH, Su, Y, Patel, S, Ramage, CL, Zhao, J, Temby, BR, Carter, JL, Edwards, H, Buck, SA, Wiley, SE, Hüttemann, M, Polin, L, Kushner, J, Dzinic, SH, White, K, Bao, X, Li, J, Yang, J, Boerner, J, Hou, Z, Al-Atrash, G, Konoplev, SN, Busquets, J, Tiziani, S, Matherly, LH, Taub, JW, Konopleva, M, Ge, Y & Baran, N 2024, 'Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro', Biochemical Pharmacology, vol. 220, 115981. https://doi.org/10.1016/j.bcp.2023.115981

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title = "Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro",

abstract = "Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.",

keywords = "Acute myeloid leukemia, ME-344, Oxidative phosphorylation, Purine biosynthesis, Venetoclax",

author = "Hurrish, {Katie H.} and Yongwei Su and Shraddha Patel and Ramage, {Cassandra L.} and Jianlei Zhao and Temby, {Brianna R.} and Carter, {Jenna L.} and Holly Edwards and Buck, {Steven A.} and Wiley, {Sandra E.} and Maik H{\"u}ttemann and Lisa Polin and Juiwanna Kushner and Dzinic, {Sijana H.} and Kathryn White and Xun Bao and Jing Li and Jay Yang and Julie Boerner and Zhanjun Hou and Gheath Al-Atrash and Konoplev, {Sergej N.} and Jonathan Busquets and Stefano Tiziani and Matherly, {Larry H.} and Taub, {Jeffrey W.} and Marina Konopleva and Yubin Ge and Natalia Baran",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2024",

month = feb,

doi = "10.1016/j.bcp.2023.115981",

language = "English (US)",

volume = "220",

journal = "Biochemical Pharmacology",

issn = "0006-2952",

publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro

AU - Hurrish, Katie H.

AU - Su, Yongwei

AU - Patel, Shraddha

AU - Ramage, Cassandra L.

AU - Zhao, Jianlei

AU - Temby, Brianna R.

AU - Carter, Jenna L.

AU - Edwards, Holly

AU - Buck, Steven A.

AU - Wiley, Sandra E.

AU - Hüttemann, Maik

AU - Polin, Lisa

AU - Kushner, Juiwanna

AU - Dzinic, Sijana H.

AU - White, Kathryn

AU - Bao, Xun

AU - Li, Jing

AU - Yang, Jay

AU - Boerner, Julie

AU - Hou, Zhanjun

AU - Al-Atrash, Gheath

AU - Konoplev, Sergej N.

AU - Busquets, Jonathan

AU - Tiziani, Stefano

AU - Matherly, Larry H.

AU - Taub, Jeffrey W.

AU - Konopleva, Marina

AU - Ge, Yubin

AU - Baran, Natalia

PY - 2024/2

Y1 - 2024/2

N2 - Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

AB - Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

KW - Acute myeloid leukemia

KW - ME-344

KW - Oxidative phosphorylation

KW - Purine biosynthesis

KW - Venetoclax

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DO - 10.1016/j.bcp.2023.115981

M3 - Article

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AN - SCOPUS:85180425571

SN - 0006-2952

VL - 220

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

M1 - 115981

ER -

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro

Abstract

Keywords

ASJC Scopus subject areas

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