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Mechanism of antineoplastic activity of lonidamine

Kavindra Nath¹, Lili Guo², Bethany Nancolas³

¹Laboratory of Molecular Imaging, Department of Radiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.

Biochimica Et Biophysica Acta

|August 8, 2016

Abstract:

Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited l-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Recent studies have demonstrated that LND potently inhibits MPC activity in isolated rat liver mitochondria (K_i 2.5μM) and cooperatively inhibits l-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K_0.5 and Hill coefficient values of 36-40μM and 1.65-1.85, respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC₅₀~7μM) than other substrates including glutamate (IC₅₀~20μM). LND inhibits the succinate-ubiquinone reductase activity of respiratory Complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through Complex II and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated l-lactic acid efflux, Complex II and glutamine/glutamate oxidation.

Insights

Lonidamine (LND) inhibits the mitochondrial pyruvate carrier (MPC), a key cancer cell target. It also affects lactate transport, Complex II, and amino acid oxidation, offering a multi-pronged anticancer strategy.

Area of Science:

Biochemistry
Oncology
Molecular Biology

Background:

Lonidamine (LND) is an established antispermatogenic agent with demonstrated anticancer properties.
LND sensitizes tumors to various cancer therapies, including chemotherapy, radiotherapy, and hyperthermia.
The precise molecular mechanisms underlying LND's anticancer effects, particularly its impact on cellular metabolism, remain incompletely understood.

Purpose of the Study:

To elucidate the specific metabolic pathways and molecular targets affected by Lonidamine (LND) in cancer cells.
To investigate the inhibitory effects of LND on key metabolic transporters and enzymes implicated in cancer bioenergetics.
To identify the most sensitive anti-tumor targets for LND action.

Main Methods:

Assessed LND's inhibition of the mitochondrial pyruvate carrier (MPC) in isolated rat liver and heart mitochondria.
Quantified LND's effect on l-lactate transport mediated by monocarboxylate transporters (MCT1, MCT2, MCT4) in Xenopus laevis oocytes.
Evaluated LND's impact on respiratory Complex II activity and cellular reactive oxygen species (ROS) generation.
Examined LND's effects on the pentose phosphate pathway and associated NADPH and glutathione production.

Main Results:

LND potently inhibits MPC activity in isolated mitochondria (Ki ~2.5 μM) and cooperatively inhibits MCT-mediated l-lactate transport (K0.5 = 36-40 μM).
LND inhibits pyruvate oxidation more effectively than other substrates in heart mitochondria and affects Complex II activity.
LND induces ROS production via Complex II and suppresses the pentose phosphate pathway, reducing NADPH and glutathione levels.

Conclusions:

Mitochondrial pyruvate carrier (MPC) inhibition represents the most sensitive anti-tumor target for LND.
LND exhibits additional inhibitory effects on MCT-mediated lactate efflux, Complex II, and glutamine/glutamate oxidation.
LND's multifaceted metabolic inhibition provides a basis for its anticancer activity and therapeutic potential.

Read full analysis

Keywords:

(31)P and (1)H magnetic resonance spectroscopy Breast cancer Doxorubicin Electron transport chain Lonidamine Melanoma Melphalan Mitochondrial pyruvate carrier Monocarboxylate transporter Ovarian cancer Prostate cancer Tumor acidification Tumor bioenergetics Xenografts

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