Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib

Abstract

Many cancer therapies produce toxic side effects whose molecular mechanisms await full elucidation. The most feared and studied side effect of chemotherapeutic drugs is cardiotoxicity. Also, skeletal muscle physiology impairment has been recorded after many chemotherapeutical treatments. However, only doxorubicin has been extensively studied for its side effects on skeletal muscle. Chemotherapeutic-induced adverse side effects are, in many cases, mediated by mitochondrial damage. In particular, trastuzumab and sunitinib toxicity is mainly associated with mitochondria impairment and is mostly reversible. Vice versa, doxorubicin-induced toxicity not only includes mitochondria damage but can also lead to a more robust and extensive cell injury which is often irreversible and lethal. Drugs interfering with mitochondrial functionality determine the depletion of ATP reservoirs and lead to subsequent reversible contractile dysfunction. Mitochondrial damage includes the impairment of the respiratory chain and the loss of mitochondrial membrane potential with subsequent disruption of cellular energetic. In a context of increased stress, AMPK has a key role in maintaining energy homeostasis, and inhibition of the AMPK pathway is one of the proposed mechanisms possibly mediating mitochondrial toxicity due to chemotherapeutics. Therapies targeting and protecting cell metabolism and energy management might be useful tools in protecting muscular tissues against the toxicity induced by chemotherapeutic drugs.

Using Machine Learning Methods and Structural Alerts for Prediction of Mitochondrial Toxicity

“…However, it is known that many different endpoints, such as the inhibition of the mitochondrial membrane potential, can lead to mitochondrial toxicity and ultimately to cell death. Especially a loss in the membrane potential can lead to increased ROS (reactive oxygen species) formation or perturbation of the energy homeostasis, thus resulting in mitochondrial toxicity and cell death . Therefore, we combined multiple datasets using the endpoint mitochondrial membrane potential as well as other assays related to mitochondrial toxicity to generate a large dataset for subsequent analysis.…”

Magnetic Temperature-Sensitive Solid-Lipid Particles for Targeting and Killing Tumor Cells

“…Consequently, anticancer remedies are needed with low general toxicity in the organism and capability to circumvent mechanisms of cellular resistance to the anticancer agents. Cytotoxicity of chemotherapeutics, including anthracyclines, platinum complexes, and topoisomerase inhibitors, is known to be related to the overproduction of ROS that causes death of cells (Yokoyama et al, 2017;Gorini et al, 2018;Yang et al, 2018). In contrast to anticancer drugs commonly used within systemic therapy, the mag.SLPs are deprived of any medicinal payload and the only source for ROS production are IOs.…”

Combined effects of avasimibe immunotherapy, doxorubicin chemotherapy, and metal–organic frameworks nanoparticles on breast cancer

“…Clinical research proved that DOX is highly toxic, and its long-term application may cause various side effects (Greish, Sawa, Fang, Akaike, & Maeda, 2004). The adverse reactions include fatigue, alopecia, nausea, vomiting, oral sores, and so forth (Gorini et al, 2018). So, a new | 4819 strategy to decrease the toxicity of DOX was developed by using pH sensitive and tumor specific nano-drug delivery system.…”