α-Lipoic acid sensitizes lung cancer cells to chemotherapeutic agents and anoikis via integrin β1/β3 downregulation

Abstract

Chemotherapeutic failure and metastasis are the main causes of high mortality rate in lung cancer. Alteration of cellular redox status in response to endogenous stimuli or exogenous compounds has a significant impact on cell signaling and behavior. Herein we divulge for the first time that lung cancer cells exposed to α-lipoic acid (LA) resulted in a higher level of cellular superoxide anion (O2·-) and hydrogen peroxide (H2O2), and such an increase of the specific reactive oxygen species (ROS) downregulated integrin β1 and β3, the integrins known for potentiating aggressive behavior and metastasis. The LA-treated cells exhibited significant decrease in their abilities to survive in detached condition and grow in anchorage-independent soft agar assay. Furthermore, LA sensitized the cells to cisplatin, etoposide and paclitaxel-induced apoptosis. For underlying mechanism, we found that the treatment of the cells with LA significantly decreased integrin β1 and β3, while had no effect on integrin α5 and αv. Interestingly, survival protein p-AKT and anti-apoptotic protein Bcl-2 were reduced in an association to such integrin modulations. Using ROS probes and selective anti-oxidants, we have shown that H2O2 and O2·- induced by LA are key players for the decrease of β1 and β3 integrins, respectively. These findings indicate a novel effect of LA as well as specific ROS, O2·- and H2O2 in integrin regulation, anoikis and chemotherapeutic sensitizations.

Phoyunnanin E inhibits migration of non-small cell lung cancer cells via suppression of epithelial-to-mesenchymal transition and integrin αv and integrin β3

“…Cancer metastasis is the multistep process of cancer cells spreading from their original site to other distant sites of the body [ 32 – 34 ]. During metastasis, cancer cells in an anchorage-independent condition are likely to die in the process of anoikis, a detachment-induced apoptosis; however, metastatic cells utilize several mechanisms to escape anoikis and consequently grow at distant sites [ 22 , 35 , 36 ]. Among several potentiating factors of metastasis, the transition of epithelial to mesenchymal phenotype, known as EMT [ 6 , 37 , 38 ], has garnered most attention [ 39 – 41 ].…”

Avicequinone B sensitizes anoikis in human lung cancer cells

“…The up-regulation of integrin β1 and β3 influences with various aggressive behaviors in cancer cells [ 36 , 37 ]. Recent study revealed that the diminution of β1 and β3 integrins suppresses survival and growth under detachment condition in human lung cancer cells [ 38 ]. Herein, suppression on integrin survival pathway in lung cancer cells induced by avicequinone B was elucidated.…”

SARS-CoV-2 attachment to host cells is possibly mediated via RGD-integrin interaction in a calcium-dependent manner and suggests pulmonary EDTA chelation therapy as a novel treatment for COVID 19

“…In combination with the EDTA/EGTAbased pulmonary chelation therapy, modulation of integrins expression using integrins inhibitors or anti-integrin antibodies could also serve as a mechanism to treat COVID-19 patients ( Henderson et al, 2013 , Hatley et al, 2018 , Sigrist et al, 2020 ). The expression of such integrins can be down regulated by modulation of intracellular redox ions such as superoxide anion (O 2 •− ) and H 2 O 2 ( Puchsaka et al, 2016 ). Besides this, some bioactive compounds/molecules such as Ouabain are also known to affect integrins expression in lung cells (Ninsontia et al, 2014).…”