Compensatory combination of mTOR and TrxR inhibitors to cause oxidative stress and regression of tumors

Abstract

Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.

Glaucocalyxin B Attenuates Ovarian Cancer Cell Growth and Cisplatin Resistance In Vitro via Activating Oxidative Stress

“…Further analysis showed that pretreatment with SP600125 partially reversed the combined treatment-induced growth inhibition in A2780 and A2780/DDP cells, suggesting that the JNK signaling pathway is essential for the synergistic action of GLB and cisplatin. ROS has been reported to activate the JNK pathway leading us to speculate that ROS may be the upstream mediator of the JNK signaling pathway [24,25]. Indeed, we found that the increased phosphorylation of JNK was greatly reversed by NAC pretreatment.…”

Cryptotanshinone Inhibits the Growth of HCT116 Colorectal Cancer Cells Through Endoplasmic Reticulum Stress-Mediated Autophagy

“…ER stress is considered a common feature in various types of blood and solid cancers (Bhardwaj et al, 2019;Xia et al, 2021). In the current study, ER stress participation was observed in the growth and proliferation of several solid tumors, including CRC cells.…”

A Novel Compound, Tanshinol Borneol Ester, Ameliorates Pressure Overload-Induced Cardiac Hypertrophy by Inhibiting Oxidative Stress via the mTOR/β-TrCP/NRF2 Pathway

“…Endoplasmic reticulum (ER) stress is also an important mechanism responsible for the pathogenesis of cardiac hypertrophy, which is maintained by unfolded protein response (UPR), an adaptive pathway that adjusts intracellular protein-folding capacity to maintain ER homeostasis and cell survival (Cominacini et al, 2015;Xiong et al, 2021). Additionally, extensive studies suggested that perturbation of intracellular oxidative homeostasis can activate ER stress with the imbalance of misfolded and unfolded protein accumulation in the ER lumen, in turn resulting in excessive ROS production and dysfunction of mitochondrial respiration, eventually exacerbating cardiomyocyte apoptosis (Wang et al, 2018;Xia et al, 2021). Although moderate ER stress restores prooxidant-antioxidant balance, maladaptive UPR activation could lead to cell dysfunction or apoptosis (Ren et al, 2021).…”