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FRI-1 Is an Anti-Cancer Isoquinolinequinone That Inhibits the Mitochondrial Bioenergetics and Blocks Metabolic Shifts
Miguel Córdova-Delgado1, Sebastián Fuentes-Retamal1,2, Charlotte Palominos1,2
1Laboratorio de Plasticidad Metabólica y Bioenergética, Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Independencia 1027, Casilla 7, Santiago 8380453, Chile.
Abstract:
Since breast cancer (BC) cells are dependent on mitochondrial bioenergetics for promoting proliferation, survival, and metastasis, mitochondria highlight as an important target for anticancer drug discovery. FRI-1, methyl 1, 3-dimethyl-5, 8-dioxo-5, 8-dihydro-4-isoquinolinecarboxylate, was previously described as a selective cytotoxic compound on cancer cell lines, however, details on the mechanism of action remain unknown. In this work, we describe that FRI-1 inhibits mitochondrial bioenergetics, producing apoptosis in MCF7 and MDA-MB-231 BC cell lines. FRI-1 decreases the maximal oxygen consumption rate (OCR), Δψm, NADH, and ATP levels, with a notable increase of mitochondrial reactive oxygen species (ROS) production, promoting AMPK activation with pro-survival effects. Moreover, FRI-1 inhibits the metabolic remodeling to glycolysis induced by oligomycin. In isolated tumoral mitochondria, FRI-1 increases Complex I and III-dependent OCR state 2, and this is sensitive to rotenone and antimycin A inhibitor additions, suggesting a redox cycling event. Remarkably, α-ketoglutarate and lipoic acid supplementation reversed and promoted, respectively, the FRI-1-induced apoptosis, suggesting that mitochondrial redox disruption affects 2-oxoglutarate dehydrogenase (OGDH) activity, and this is involved in their anticancer mechanism. Consistent with this, the combination of FRI-1 and CPI-613, a dual inhibitor of redox-sensible tricarboxylic acid (TCA) cycle enzymes PDH and OGDH, produced extensive BC cell death. Taken together, our results suggest that FRI-1 exhibits anticancer effects through inhibition of mitochondrial bioenergetics by redox disruption in BC cells.
Insights
FRI-1, a novel compound, targets breast cancer cell mitochondria, inhibiting energy production and inducing apoptosis. This mechanism involves disrupting mitochondrial redox balance and affecting key metabolic enzymes, offering a new avenue for breast cancer therapy.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Breast cancer (BC) cell proliferation, survival, and metastasis are critically dependent on mitochondrial bioenergetics.
- Mitochondria represent a promising target for novel anticancer drug discovery.
- The precise mechanism of action for the cytotoxic compound FRI-1 in cancer cells was previously unknown.
Purpose of the Study:
- To elucidate the mechanism of action of FRI-1 as an anticancer agent.
- To investigate FRI-1's effects on mitochondrial bioenergetics in breast cancer cells.
- To explore the role of mitochondrial redox disruption in FRI-1's anticancer activity.
Main Methods:
- Assessed mitochondrial bioenergetics, including oxygen consumption rate (OCR), mitochondrial membrane potential (Δψm), NADH, ATP levels, and reactive oxygen species (ROS) production in MCF7 and MDA-MB-231 BC cell lines.
- Investigated the effect of FRI-1 on glycolysis and mitochondrial Complex I and III activity.
- Utilized α-ketoglutarate and lipoic acid supplementation, and combined FRI-1 with CPI-613 (a dual inhibitor of PDH and OGDH) to evaluate the role of OGDH activity and redox disruption.
Main Results:
- FRI-1 significantly inhibited mitochondrial bioenergetics, decreasing OCR, Δψm, NADH, and ATP levels while increasing mitochondrial ROS production.
- FRI-1 induced apoptosis in breast cancer cells and inhibited oligomycin-induced metabolic remodeling to glycolysis.
- Evidence suggests FRI-1 induces a redox cycling event involving Complex I and III, disrupts 2-oxoglutarate dehydrogenase (OGDH) activity, and its combination with CPI-613 leads to extensive BC cell death.
Conclusions:
- FRI-1 exhibits anticancer effects by inhibiting mitochondrial bioenergetics through redox disruption in breast cancer cells.
- The mechanism involves targeting mitochondrial respiration and potentially impacting OGDH activity.
- FRI-1 represents a potential therapeutic agent for breast cancer, warranting further investigation.
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