Artesunate Inhibits the Cell Growth in Colorectal Cancer by Promoting ROS-Dependent Cell Senescence and Autophagy

Abstract

Although artesunate has been reported to be a promising candidate for colorectal cancer (CRC) treatment, the underlying mechanisms and molecular targets of artesunate are yet to be explored. Here, we report that artesunate acts as a senescence and autophagy inducer to exert its inhibitory effect on CRC in a reactive oxygen species (ROS)-dependent manner. In SW480 and HCT116 cells, artesunate treatment led to mitochondrial dysfunction, drastically promoted mitochondrial ROS generation, and consequently inhibited cell proliferation by causing cell cycle arrest at G0/G1 phase as well as subsequent p16- and p21-mediated cell senescence. Senescent cells underwent endoplasmic reticulum stress (ERS), and the unfolded protein response (UPR) was activated via IRE1α signaling, with upregulated BIP, IRE1α, phosphorylated IRE1α (p-IRE1α), CHOP, and DR5. Further experiments revealed that autophagy was induced by artesunate treatment due to oxidative stress and ER stress. In contrast, N-Acetylcysteine (NAC, an ROS scavenger) and 3-Methyladenine (3-MA, an autophagy inhibitor) restored cell viability and attenuated autophagy in artesunate-treated cells. Furthermore, cellular free Ca2+ levels were increased and could be repressed by NAC, 3-MA, and GSK2350168 (an IRE1α inhibitor). In vivo, artesunate administration reduced the growth of CT26 cell-derived tumors in BALB/c mice. Ki67 and cyclin D1 expression was downregulated in tumor tissue, while p16, p21, p-IRE1α, and LC3B expression was upregulated. Taken together, artesunate induces senescence and autophagy to inhibit cell proliferation in colorectal cancer by promoting excessive ROS generation.

The Role of Oxidative Stress in Tumorigenesis and Progression

“…As one of the hinges of the cellular stress response, mitochondria play a pivotal role in oxidative stress and stress-induced premature senescence. In colorectal cancer cells, artesunate treatment-induced mitochondrial dysfunction can drastically spur mitochondrial ROS generation, thereby promoting cell senescence [ 112 ], which has become a vital target of cancer therapy [ 113 ].…”

Anti-Cancer Effects of Artesunate in Human 3D Tumor Models of Different Complexity

“…Human colorectal cancer cell lines HCT-116 and HT-29 were selected because of their reported sensitivity towards Artesunate [61,62] and their spheroid formation ability [63][64][65]. Cell lines were purchased from ATCC (HCT-116, ATCC CCL-247; HT-29, ATCC HTB-38) and cultured according to the manufacturer's instructions.…”

Combined Photothermal/Combination Chemotherapeutic Approach Using Zif-8-Supported Artesunate and Gold Nanorods

“…The peroxide bridges in these structures undergo cleavage, causing harm to the cells. 16 To enhance the precision of ART in targeting tumor cells, a drug that accumulates in the mitochondria of cells was added. The mitochondria, which function as cell energy generators, play essential roles in supplying cellular fuel and regulating diverse cellular mechanisms, including cell specialization, programmed cell death, signal transmission, and calcium balance.…”

“…The notable tolerability of artesunate (ART) as an anticancer medication deserves attention. − When exposed to acidic conditions. The peroxide bridges in these structures undergo cleavage, causing harm to the cells . To enhance the precision of ART in targeting tumor cells, a drug that accumulates in the mitochondria of cells was added.…”