Small molecules regulating reactive oxygen species homeostasis for cancer therapy

Abstract

Elevated intracellular reactive oxygen species (ROS) and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. Compared with normal cells, cancer cells exhibit increased ROS to maintain their malignant phenotypes and are more dependent on the “redox adaptation” mechanism. Thus, there are two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to prevent or treat cancer. The first strategy, that is, chemoprevention, is to prevent or reduce intracellular ROS either by suppressing ROS production pathways or by employing antioxidants to enhance ROS clearance, which protects normal cells from malignant transformation and inhibits the early stage of tumorigenesis. The second strategy is the ROS‐mediated anticancer therapy, which stimulates intracellular ROS to a toxicity threshold to activate ROS‐induced cell death pathways. Therefore, targeting the regulation of intracellular ROS‐related pathways by small‐molecule candidates is considered to be a promising treatment for tumors. We herein first briefly introduce the source and regulation of ROS, and then focus on small molecules that regulate ROS‐related pathways and show efficacy in cancer therapy from the perspective of pharmacophores. Finally, we discuss several challenges in developing cancer therapeutic agents based on ROS regulation and propose the direction of future development.

Targeting Jab1 using hesperidin (dietary phytocompound) for inducing apoptosis in HeLa cervical cancer cells

“…Targeting these characteristics has been recognized as potential therapeutic approaches to cancer prevention and treatment. Apart from these conventional approaches, utilization of dietary sources is gaining wider attention in regulating these crucial events associated with cancer progression (Rodriguez‐Mateos et al., 2014; Zhang et al., 2021).…”

Discovery of hydroxytyrosol as thioredoxin reductase 1 inhibitor to induce apoptosis and G1/S cell cycle arrest in human colorectal cancer cells via ROS generation

“…Since excess ROS levels could be cytotoxic ( 35 ), apoptosis was examined using Annexin V/PI double staining assay. A significant increase in the percentage of apoptotic cells was detected after HT treatment for 24 h in HCT-116 and SW620 cells ( Fig.…”

“…This system plays a role in maintaining H 2 O 2 levels in cells via the conversion of H 2 O 2 to H 2 O. Trx contains two adjacent thiols in its reduced form that are converted to a disulfide bond in the oxidized form ( 39 ). The oxidized Trx is then recycled back into the reduced form by TrxR1 and NADPH ( 35 ). The present study demonstrated that HT could significantly inhibit both recombinant and cellular TrxR1 enzyme activity.…”

Onopordopicrin from the new genus Shangwua as a novel thioredoxin reductase inhibitor to induce oxidative stress-mediated tumor cell apoptosis

“…We then explored the mechanism by which ONP induced HeLa apoptosis and showed selective inhibition of tumor cell growth. Considering that one of the biochemical characteristics of carcinoma cells is that they exhibit a higher level of oxidative stress than normal cells, and further stimulation by cytotoxic agents leads to preferentially induce tumor cell apoptosis 10,49 . We thus observed the changes in ROS levels in HeLa cells treated with ONP to validate the elevated oxidative stress level is the mechanism by which ONP selectively induces tumor cell apoptosis.…”

“…Alteration of redox homeostasis is a hallmark of cancer cells 10 . Thioredoxin reductase (TrxR) enzymes as a critical player in regulating cellular redox signaling are increasingly recognized as attractive targets for anticancer drugs [11][12][13][14][15][16] .…”