Mitochondria Determine the Efficacy of Anticancer Agents that Interact with DNA but Not the Cytoskeleton

Abstract

Although chemotherapy is an important method for the treatment of patients with cancer, its efficacy is limited because of different sensitivities of tumor cells to anticancer agents and/or side effects on normal tissues. The present work demonstrates that mitochondria play a crucial role in the apoptosis of cancer cells induced by anticancer agents that interact with DNA but not with the cytoskeleton. Agents that interact with DNA selectively enhanced generation of reactive oxygen species (ROS) in mitochondria, released cytochrome c, and activated caspase-9 and caspase-3 to induce apoptosis of mesothelioma H2052 cells but not their 0 cells, which lack mitochondrial DNA (mtDNA). The sensitivity of a variety of cells to the agents showed positive correlation with the amounts of their mitochondria. In contrast, agents that selectively affect the cytoskeleton activated caspase-8 and caspase-3 and equally induced apoptosis of both H2052 and their 0 cells by a mitochondria-independent mechanism. The results suggest that mtDNA is a potential target for the anticancer agents that interact with DNA to induce ROS-dependent apoptosis of cancer cells, whereas agents that affect the cytoskeleton induce cell death by a mitochondria-and ROS-independent mechanism. The present observation is important for the selection of medicine for chemotherapy of patients with cancer.

Computational modeling of apoptotic signaling pathways induced by cisplatin

“…FasL activates the initiator caspase-8 (Figure 2A, B), and then activated caspase-8 leads directly to the activation of downstream caspase-3, causing apoptosis (Figure 2C) [29]. Similar to previous experiments of cisplatin-induced cell death [44,45]; all variable curves were plotted until 24 h after uptake of cisplatin. To evaluate the interaction between activated caspase-8 and caspase-3 activation or apoptosis, we tested our mathematical model for different levels of activated caspase-8 expression.…”

Oxoaporphine Metal Complexes (CoII, NiII, ZnII) with High Antitumor Activity by Inducing Mitochondria-Mediated Apoptosis and S-phase Arrest in HepG2

“…Caspase family is closely related to the cell apoptosis via the mitochondrial pathway52, especially caspases-3, -8 and -9. To better understand the antitumor mechanisms, it needs to confirm whether caspase-3, -8 and -9 are activated when the tumor cells are treated with 1–3 .…”

Targeting Cancer Cell Mitochondria as a Therapeutic Approach

“…Furthermore, it has been demonstrated that mtDNA is an important target of multiple anticancer drugs that interact with DNA, and that mitochondria determine the efficacy of this class of anticancer drugs [4]. Several approaches have been developed as possible means to selectively kill cancer cells based on their mitochondrial dysfunction and metabolic alterations.…”