Recent advances in molecular mechanisms of anticancer natural products that target mitochondrial bioenergetics

Although previously it was considered that cancer cells had high glycolysis and mitochondrial impairment, recent evidence has revealed that several events during tumorigenesis such as chemoresistance and metastasis are dependent on mitochondrial function. This converts mitochondria into a promising target for new anticancer strategies. In this chapter, we analyzed selected examples of natural products (NPs) isolated from diverse sources such as bacteria, fungi, marine sponges, plants, and snake venom that promote cell death and inhibition of the proliferation and migration/invasion of malignant cells through the induction of mitochondrial dysfunction. Some of them act directly inhibiting oxidative phosphorylation by (1) interaction with respiratory complexes and other ones affect indirectly the oxidative phosphorylation by (2) modulating the mitochondrial Ca2+ uptake, (3) controlling the glucose-derived pyruvate oxidation by modulation of PDK/PDH axis, (4) disrupting the inner mitochondrial membrane integrity and fluidity by interaction with cardiolipin, or (5) promoting changes in the quality control of mitochondria. Several NP derivatives that incorporate a triphenylphosphonium cation as a mitochondrial drug delivery system have been described whose anticancer effects occur by inhibitions of Complex I, oxoglutarate dehydrogenase, thioredoxin reductase, ATP synthase, and mitochondrial potassium Kv1.3 channel. The recent advances in the mechanisms of action of natural compounds that inhibit the proliferation of cancer stem cells, a relevant type of tumor-initiating cells involved in the chemoresistance and tumor relapse, are discussed in detail. Notably, NPs offer the opportunity to discover innovative chemical structures and unexpected mechanisms of action on cancer mitochondrial bioenergetics with promising anticancer approaches.