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OXPHOS-targeting drugs in oncology: new perspectives
Balaraman Kalyanaraman1, Gang Cheng1, Micael Hardy2
1Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
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.
Insights
Mitochondria-targeted drugs show promise for cancer treatment. Triphenylphosphonium cation (TPP+)-based drugs selectively target cancer cell mitochondria, inhibiting proliferation with minimal toxicity, offering a new therapeutic strategy.
Area of Science:
- Mitochondrial medicine
- Cancer therapeutics
- Drug development
Background:
- Mitochondria-targeted drugs are emerging as promising antitumor therapeutics.
- Clinical toxicity has been observed with some mitochondria-targeting drugs.
- Developing modified natural compounds and FDA-approved drugs with enhanced therapeutic indices is a key strategy.
Purpose of the Study:
- To discuss mitochondria-targeted modified natural compounds and FDA-approved drugs as an alternative strategy for cancer therapy.
- To highlight the potential of Triphenylphosphonium cation (TPP+)-based drugs in cancer treatment.
- To emphasize the need for clinical translation of these novel therapeutics.
Main Methods:
- Selective accumulation of TPP+-based drugs in cancer cell mitochondria due to altered membrane potential.
- Targeting of oxidative phosphorylation proteins within the mitochondrial electron transport chain.
- Inhibition of mitochondrial respiration and tumor proliferation.
Main Results:
- TPP+-based drugs selectively accumulate in mitochondria, inhibiting tumor proliferation.
- These drugs exhibit minimal toxic side effects in preclinical models and humans.
- TPP+-based agents can sensitize cancer cells to radiation and immunotherapies.
Conclusions:
- TPP+-based drugs represent a novel class of oxidative phosphorylation inhibitors with anticancer potential.
- Synthesized from natural products and FDA-approved drugs, these agents show low toxicity in preclinical studies.
- Clinical translation of TPP+-based OXPHOS-inhibiting drugs is warranted for cancer prevention and treatment.
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