Antimycin A shows selective antiproliferation to oral cancer cells by oxidative stress‐mediated apoptosis and DNA damage

Abstract

The antibiotic antimycin A (AMA) is commonly used as an inhibitor for the electron transport chain but its application in anticancer studies is rare. Recently, the repurposing use of AMA in antiproliferation of several cancer cell types has been reported. However, it is rarely investigated in oral cancer cells. The purpose of this study is to investigate the selective antiproliferation ability of AMA treatment on oral cancer cells. Cell viability, flow cytometry, and western blotting were applied to explore its possible anticancer mechanism in terms of both concentration-and exposure time-effects. AMA shows the higher antiproliferation to two oral cancer CAL 27 and Ca9-22 cell lines than normal oral HGF-1 cell lines. Moreover, AMA induces the production of higher reactive oxygen species (ROS) levels and pan-caspase activation in oral cancer CAL 27 and Ca9-22 cells than in normal oral HGF-1 cells, providing the possible mechanism for its selective antiproliferation effect of AMA. In addition to ROS, AMA induces mitochondrial superoxide (MitoSOX) generation and depletes mitochondrial membrane potential (MitoMP). This further supports the AMA-induced oxidative stress changes in oral cancer CAL 27 and Ca9-22 cells. AMA also shows high expressions of annexin V in CAL 27 and Ca9-22 cells and cleaved forms of poly (ADP-ribose) polymerase (PARP), caspase 9, and caspase 3 in CAL 27 cells, supporting the apoptosis-inducing ability of AMA. Furthermore, AMA induces DNA damage (γH2AX and 8-oxo-2 0-deoxyguanosine [8-oxodG]) in CAL

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management

“…It has been also identified as target for anticancer drugs. Antimycin A is the most classic CIII inhibitor to trigger apoptosis for effectively eliminating cancer cells [ 263 , 264 ]. Resveratrol, a plant-derived polyphenol, exhibited considerable antitumor efficacy by efficiently inhibiting ETC complexes, especially CIII to induce apoptosis and disturb multiple cellular processes in primary and resistant cancer cells [ 265 – 267 ].…”

Acrylamide, acrylic acid, or 2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid induced cytotoxic in Photobacterium phosphoreum, PC12, and SK‐N‐SH cells

“…In the present study, we found that AA or ACR could induce G0/G1 phase arrest in both PC12 cells and SK‐N‐SH cells, interestingly they caused significant different phase decreases in the PC12 and SK‐N‐SH cells, G2/M phase and S phase, respectively. Even the same reagent may induce different cell cycle arrest responses in different cells 44 . ACR was a water solubility monomer that could be easily entered the body and even could effectively traverse the blood–brain barrier and the placental barrier 28,45–47 .…”

“…ACR could directly combine with the cellular antioxidant biomarker GSH, decrease the GSH content, disturb the intracellular redox balance and cause ROS accumulation 47 . ROS could generate DNA damage involving 8‐OHdG and DNA double‐strand breaks, and even cause apoptosis 39,44,49 . ACR was reported to generate genotoxicity through depletion of GSH causing intracellular ROS to induce oxidative DNA damage 50 .…”

“…Even the same reagent may induce different cell cycle arrest responses in different cells. 44 ACR was a water solubility monomer that could be easily entered the body and even could effectively traverse the blood-brain barrier and the placental barrier. 28,[45][46][47] ACR has a weak interaction with DNA.…”

Roles of Mitochondria in Oral Squamous Cell Carcinoma Therapy: Friend or Foe?

“…For example, azoxystrobin, an inhibitor of complex III, could suppress cell proliferation and cause MAP of OSCC cells by promoting mtROS formation [ 13 ]. In addition, antimycin A, another inhibitor of complex III, could also lead to the MAP of OSCC cells by inducing the production of mtROS [ 84 ]. Interestingly, ROS can influence Bcl-2 family proteins by regulating their phosphorylation and ubiquitination through many signaling pathways [ 85 , 86 ].…”