Curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC) through the induction of ferroptosis via the ADAMTS18 gene

Abstract

Background:To explore the possible mechanism by which curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC).Methods: A sunitinib-resistant ccRCC cell model was established. The MTT assay was used to determine the half maximal inhibitory concentration (IC 50 ) and drug resistance (DR) index. The effects of curcumin plus sunitinib or sunitinib alone on drug-resistant cell lines were verified by the cell counting kit-8 (CCK-8) assay, colony formation assay, and apoptosis assay. The concentration of iron ions in the cell lines was analyzed using an Abcam Iron Assay Kit. The expressions of ADAMTS18 gene and ferroptosis-related proteins (NCOA4, FTH1 and p53) after curcumin plus sunitinib treatment were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. After transfection of curcumin plus sunitinib/sunitinib alone-treated drug-resistant cell lines with si-ADAMTS18, cell proliferation activity was assessed by the CCK-8 assay, and the protein expression levels of ADAMTS18, NCOA1, FTH1 and p53 were analyzed by Western blotting. After treatment with ferroptosis-1 (Fer-1; a ferroptosis inhibitor), the cell proliferation activity of drug-resistant cell lines treated with curcumin plus sunitinib/sunitinib alone was reassessed using the CCK-8 assay.Results: Curcumin plus sunitinib inhibited the proliferation of sunitinib-resistant ccRCC cells (P<0.05).Curcumin significantly decreased the concentration of iron ions and increased the expression of ADAMTS18 gene, while significantly inhibited ferroptosis-related protein expression (P<0.05). After silencing the ADAMTS18 gene, there was no significant difference in cell proliferation or ferroptosis-related protein expression between curcumin plus sunitinib and sunitinib-treated drug-resistant cell lines (P>0.05).Ferroptosis inhibitors reversed the inhibitory effect of curcumin on sunitinib-resistant ccRCC cell lines.Conclusions: Curcumin can reverse the sunitinib resistance in ccRCC, possibly by upregulating the expression of the ADAMTS18 gene to induce ferroptosis.

The Role of Ferroptosis and Cuproptosis in Curcumin against Hepatocellular Carcinoma

“…For example, in NSCLC, curcumin could induce ferroptosis via autophagic activation to improve the therapeutic efficacy [ 18 ]. In ccRCC, curcumin promoted ferroptosis to reverse sunitinib resistance [ 19 ]. In breast cancer, curcumin suppressed tumorigenesis via enhancing SLC1A5-mediated ferroptosis [ 21 ].…”

“…Ferroptosis, identified and named a decade ago, is a unique type of programmed cell death primarily driven by iron-dependent lipid peroxidation [ 16 , 17 ]. Growing evidence has revealed that ferroptosis plays a crucial part in treatment with curcumin against various cancers, such as non-small-cell lung cancer (NSCLC) [ 18 ], clear cell renal cell carcinoma (ccRCC) [ 19 ], and breast cancer [ 20 , 21 ]. Despite these findings, however, the precise action of curcumin-modulated ferroptosis in HCC remains unclear.…”

Review and Chemoinformatic Analysis of Ferroptosis Modulators with a Focus on Natural Plant Products

“…Curcumin reversed resistance and enhanced the sensitivity of 786-O-DR (drug-resistant) cells to sunitinib. It reduced the iron content, upregulated the expression of the ADAMTS18 gene, and significantly reduced expression levels of the ferritin autophagic cargo receptor NCOA4 (nuclear receptor coactivator 4) and the proteins FTH1 and p53 in the cells [ 134 ].…”

Novel Insight into Ferroptosis in Kidney Diseases

“…STEAP3 influences ferroptosis and RCC progression via the p53/xCT pathway [63]. Studies have demonstrated that [129]. Icariside II caused ferroptosis via modulation of the miR-324-3p/GPX4 axis in RCC cells [130].…”

“…Kerimoglu et al [128] revealed that the cyst(e)inase-rapamycin combination caused ferroptosis in both in vitro and in vivo models of hereditary leiomyomatosis and RCC. Evidence indicated that curcumin made ccRCC less resistant to sunitinib by causing ferroptosis through ADAMTS18 to treat ccRCC [129]. Icariside II caused ferroptosis via modulation of the miR-324-3p/GPX4 axis in RCC cells [130].…”