Artesunate Inhibits Growth of Sunitinib-Resistant Renal Cell Carcinoma Cells through Cell Cycle Arrest and Induction of Ferroptosis

Abstract

Although innovative therapeutic concepts have led to better treatment of advanced renal cell carcinoma (RCC), efficacy is still limited due to the tumor developing resistance to applied drugs. Artesunate (ART) has demonstrated anti-tumor effects in different tumor entities. This study was designed to investigate the impact of ART (1–100 µM) on the sunitinib-resistant RCC cell lines, Caki-1, 786-O, KTCTL26, and A-498. Therapy-sensitive (parental) and untreated cells served as controls. ART’s impact on tumor cell growth, proliferation, clonogenic growth, apoptosis, necrosis, ferroptosis, and metabolic activity was evaluated. Cell cycle distribution, the expression of cell cycle regulating proteins, p53, and the occurrence of reactive oxygen species (ROS) were investigated. ART significantly increased cytotoxicity and inhibited proliferation and clonogenic growth in both parental and sunitinib-resistant RCC cells. In Caki-1, 786-O, and A-498 cell lines growth inhibition was associated with G0/G1 phase arrest and distinct modulation of cell cycle regulating proteins. KTCTL-26 cells were mainly affected by ART through ROS generation, ferroptosis, and decreased metabolism. p53 exclusively appeared in the KTCTL-26 cells, indicating that p53 might be predictive for ART-dependent ferroptosis. Thus, ART may hold promise for treating selected patients with advanced and even therapy-resistant RCC.

Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis

“…Lack of studies also increases the risk of unidentified contraindications and adverse side effects of the natural compounds combined with conventional therapy [ 14 ]. However, some studies have been carried out indicating antitumor effects of natural compounds, notably if applied together with an established therapy or by counteracting therapy resistance [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Development and Validation of a Robust Ferroptosis-Related Prognostic Signature to Predict Overall Survival in Clear Cell Renal Cell Carcinoma

“…It has recently been shown that promotion of ferroptosis could be exploited to treat cancer, and ferroptosis inducers exhibited great potential to improve therapeutic performance [16,19] . For instance, Markowitsch et al have demonstrated that artesunate could inhibit growth of sunitinib-resistant renal cell carcinoma cells through cell cycle arrest and induction of ferroptosis [20] . Sulfasalazine, a system xc-inhibitor, could inhibit cysteine uptake and lead to ferroptosis of glioma cells [21] .…”

Progress on the study of the anticancer effects of artesunate (Review)

“…There is considerable evidence that ART can exert anticancer effects on several types of cancer cells (6,15). ART has been reported to induce apoptosis, differentiation and autophagy in colorectal cancer cells by impairing angiogenesis (27), inhibiting cell invasion and migration (28), inducing cell cycle arrest (11), upregulating ROS levels, regulating signal transduction [for example, activating the AMPK-mTOR-Unc-51-like autophagy activating kinase (ULK1) pathway in human bladder cancer cells] (9) and blocking immune escape (29). In addition, ART has been shown to restore the sensitivity of a number of cancer types to chemotherapeutic drugs by modulating various signaling pathways; for example, ART can improve the apoptosis of HCC by inhibiting the PI3K/AKT/mTOR pathway (30), and can increase liver cancer cell sensitivity to sorafenib via suppression of the MEK/ERK pathway (31) (Fig.…”

“…ART inhibits the proliferation of bladder cancer cells (RT4, RT112, T24 and TCCSup), which is associated with G 0 /G 1 -phase cell cycle arrest and downregulation of cell cycle regulatory proteins [cyclin D1 and CDK4 (required for entry into the G 1 phase); CDK1 and cyclinA/B (essential during the late S phase and early M phase)] (10). ART can block cell cycle progression and lead to a significant reduction in the levels of the cell cycle activating proteins cyclin A, cyclin B, and CDK1, evoking G 0 /G 1 phase arrest and inhibiting growth of the cells in renal cell carcinoma (11). In breast cancer cells (MCF-7 and MDA-MB-231), ART can block G 2 /M progression by upregulating beclin-1 expression, which promotes autophagy (53).…”

“…For instance, ART has been reported to induce apoptosis and autophagy in human bladder cancer cells (9,10). Moreover, it can induce cell cycle arrest, reactive oxygen species (ROS) generation and ferroptosis in renal cell carcinoma (11). In the present review, the potential anticancer effects of ART and the underlying mechanism of action involved are summarized.…”