OXPHOS-targeting drugs in oncology: new perspectives

Figures & data

Figure 1. Chemical structures of MTDs.

Figure 2. Selective uptake of TPP⁺-based MTDs into tumor mitochondria. Reprinted (adapted) with permission from Zielonka J, Joseph J, Sikora A, Hardy M, Ouari O, Vasquez-Vivar J, Cheng G, Lopez M, Kalyanaraman B. Mitochondria-targeted triphenylphosphonium-based compounds: syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chemical reviews. 2017;117(15):10043 –10,120. Copyright 2017 American Chemical Society.

Table 1. Potency and toxicity of selected mitochondria-targeted drugs in different cancers.

Compound	Cancer Type	Molecular Target & Mechanism	Preclinical Model	Toxicity & Beneficial Effects	Refs.
MitoQ	Pancreatic, breast	Complex I in the METC; respiration and ATP inhibition	Breast tumors, pancreatic tumor regression in mice xenografts	No known toxicity in preclinical models or in humans; improves vascular function, muscle weakness, and atrophy	[14–25]
Mito-HNK	Lung	Complex I in the METC; ATP inhibition, TME reprogramming	Primary tumor regression in lung cancer mice xenografts, brain metastasis inhibition	No toxicity in mice at levels 20× effective dose; no neurotoxicity, no hypothermia	[26]
Mito-MGN	Melanoma	Complex I in the METC; respiration inhibition, AMPK activation, cell cycle inhibition	Melanoma progression inhibition in a murine xenograft model	No observable toxicity in kidney in C57BL6 mice; elevated liver enzymes suggest some liver toxicity	[27,28]
Mito-ATO	Breast, brain	Complexes I and III in the METC; respiration inhibition, TME reprogramming	Enhanced antitumor activity of PD‐1 blockade in a resistant B16F10 mouse melanoma model	No kidney toxicity	[29,30]
Mito-LND	Lung	Complexes I and II in the METC; respiration inhibition, AMPK activation, mTOR inhibition	Primary lung cancer and brain metastasis regression	No toxicity in mice even at levels 200× the effective antitumor concentration	[31]
IACS-010759	Multiple myeloma, melanoma	Complex I in the METC; respiration inhibition, AMPK activation	Improved survival of mice bearing MAPKi-resistant intracranial melanoma xenografts, MBM formation inhibition in a spontaneous MBM model	Decreased body temperature and increased neuropathy in cancer patients and mice xenografts	[32]
IM156	Glioblastoma, gastric, lymphoma	Complex I in the METC; respiration inhibition, ATP production, AMPK activation, mTOR inhibition		No dose-limiting toxicity in humans (<1,200 mg) in a phase I clinical study	[33,34]
Mito-Mets	Pancreatic	Complex I in the METC; respiration inhibition, AMPK activation, mTOR inhibition	Pancreatic cancer regression in mice xenografts	No noticeable toxicity in mice	[35–37]
Mito-HU	Colon	Complexes I and III in METC; respiration inhibition	No animal studies		[38]
Mito-Tamoxifen	Breast	Complex I in the METC; depolarization of mitochondrial membrane; disruption of respiratory supercomplexes in HER2 high breast tumors	Syngeneic tumor growth inhibition with NeuTL cells derived from spontaneous HER2 high breast carcinoma in FVB/N c-neu mice	Showed a very favorable toxicity profile in preclinical testing and has progressed to phase I clinical trials	[39,40]
Mito-Curcuminoids	Breast, lung	Akt and STAT3 phosphorylation inhibition, TrxR2			[41,42]
Mito-Furocoumarins	Pancreatic	Block the mitochondrial potassium channel, enhancing apoptosis of tumor cells			[43]
Mito-DCA	Prostate	Respiration, lactic acid production and ATP inhibition	Enhanced antitumor activity of anti-PD-1 in syngeneic tumor models		[44,45]

AMPK, AMP-activated protein kinase; MAPKi, mitogen-activated protein kinases inhibitor; MBM, melanoma brain metastases; METC, mitochondrial electron transport chain; mTOR, mammalian target of rapamycin; PD-1, programmed death-1; TME, tumor microenvironment.

Figure 3. Comparisons of MTDs and the corresponding parent compounds on cell proliferation inhibitions in human pancreatic cancer (MiaPaca-2) cells. The effects of MTDs and their parental compounds on the proliferation of MiaPaCa-2 cells were monitored in the IncuCyte Live-cell Analysis system. The IC₅₀ values were determined at the point at which control cells reached ~ 90% confluence. Relative cell confluence (control is taken as 100%) is plotted against concentration. Dashed lines represent the fitting curves used to determine the IC₅₀ values as indicated. The fold of differences as indicated were calculated by the potency difference of the IC₅₀ values between each mitochondria-targeted drug and its parental compound. The IC₅₀ values of Mito-Met and metformin were published previously in Cancer Research (Cheng G et al., cancer Res, 2016). The IC₅₀ values of Mito-ATO and ATO were published in Scientific Reports (Cheng G et al., Scientific Reports, 2020; Cheng G et al., Scientific Reports, 2022). This figure is re-used under CC by 4.0 from Cheng G, Hardy M, Kalyanaraman B. Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells. Scientific Reports. 2023;13:7254.

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