Mitochondria as therapeutic targets for cancer stem cells

Abstract

Cancer stem cells (CSCs) are maintained by their somatic stem cells and are responsible for tumor initiation, chemoresistance, and metastasis. Evidence for the CSCs existence has been reported for a number of human cancers. The CSC mitochondria have been shown recently to be an important target for cancer treatment, but clinical significance of CSCs and their mitochondria properties remain unclear. Mitochondriatargeted agents are considerably more effective compared to other agents in triggering apoptosis of CSCs, as well as general cancer cells, via mitochondrial dysfunction. Mitochondrial metabolism is altered in cancer cells because of their reliance on glycolytic intermediates, which are normally destined for oxidative phosphorylation. Therefore, inhibiting cancer-specific modifications in mitochondrial metabolism, increasing reactive oxygen species production, or stimulating mitochondrial permeabilization transition could be promising new therapeutic strategies to activate cell death in CSCs as well, as in general cancer cells. This review analyzed mitochondrial function and its potential as a therapeutic target to induce cell death in CSCs. Furthermore, combined treatment with mitochondriatargeted drugs will be a promising strategy for the treatment of relapsed and refractory cancer.

Reactive oxygen species in redox cancer therapy

“…The mitochondrial DNA is targeted by ROS due to its close proximity to the ETC, where the majority of ROS are produced [55]. Instead of reducing ROS, compounds targeting cancer mitochondria trigger the overproduction of ROS, thereby inducing mitochondrial permeability transition (MPT), disturbing mitochondrial transmembrane potential, and eventually disrupting the cancer cell mitochondria [56,57]. Taken together, cancer cells are sensitive to redox disruption, and targeting either induction or reduction of ROS levels in cancer cells can lead to effective cancer treatments.…”

The Histone Demethylase KDM5 Activates Gene Expression by Recognizing Chromatin Context through Its PHD Reader Motif

“…Because standard therapies target rapidly dividing cells, this results in KDM5A and KDM5B overexpressing tumors being difficult to treat. Slow-growing KDM5 overexpressing tumor cells are also metabolically distinct from other tumor cells because they generate ATP through oxidative phosphorylation in the mitochondria and not via aerobic glycolysis (Roesch et al, 2013; Song et al, 2015). KDM5 proteins may therefore regulate fundamental metabolic processes related to energy production through unknown molecular mechanisms.…”

A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells

“…[4] Thes ignificance of mitochondrial function to CSC regulation is highlighted by the fact that unlike normal stem cells,C SCs have ah igher mitochondrial mass than bulk cancer cells. [5] Therefore, inhibiting CSC-specific modifications in mitochondrial metabolism, increasing ROSp roduction, or stimulating mitochondrial membrane depolarization with at argeted approach could offer an ew therapeutic strategy to activate cell death in CSCs as well as in general cancer cells.T he delivery of therapeutic (and imaging) agents to mitochondria is widely achieved by tethering to lipophilic (Log P > À1.7) and cationic (Z > 0) moieties,such as atriphenylphosphonium group.…”