TY - JOUR
T1 - OXPHOS-targeting drugs in oncology
T2 - new perspectives
AU - Kalyanaraman, Balaraman
AU - Cheng, Gang
AU - Hardy, Micael
AU - You, Ming
N1 - Funding Information:
This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N91019D00020, R01CA232433, and R01CA208648, and in part from the International Research Project SuperO2 from CNRS, France. Thank you to Lydia Washechek for preparing and proofreading the manuscript.
Publisher Copyright:
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023
Y1 - 2023
N2 - Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas covered: Triphenylphosphonium cation (TPP+)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP+-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert opinion: TPP+-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP+-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP+-based OXPHOS-inhibiting drugs in cancer prevention and treatment.
AB - Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas covered: Triphenylphosphonium cation (TPP+)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP+-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert opinion: TPP+-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP+-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP+-based OXPHOS-inhibiting drugs in cancer prevention and treatment.
KW - Mitochondrial targets
KW - mitochondrial therapeutics
KW - tumor cells
KW - tumor metastasis
KW - tumor xenografts
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U2 - 10.1080/14728222.2023.2261631
DO - 10.1080/14728222.2023.2261631
M3 - Review article
C2 - 37736880
AN - SCOPUS:85173986031
SN - 1472-8222
VL - 27
SP - 939
EP - 952
JO - Expert Opinion on Therapeutic Targets
JF - Expert Opinion on Therapeutic Targets
IS - 10
ER -