Curcumin-Mediated Resistance to Lenvatinib via EGFR Signaling Pathway in Hepatocellular Carcinoma

被引:11
|
作者
Miyazaki, Katsuki [1 ,2 ]
Morine, Yuji [2 ]
Xu, Caiming [1 ]
Nakasu, Chiharu [2 ]
Wada, Yuma [2 ]
Teraoku, Hiroki [2 ]
Yamada, Shinichiro [2 ]
Saito, Yu [2 ]
Ikemoto, Tetsuya [2 ]
Shimada, Mitsuo [2 ]
Goel, Ajay [1 ]
机构
[1] City Hope Comprehens Canc Ctr, Beckman Res Inst, Dept Mol Diagnost & Expt Therapeut, Duarte, CA 91010 USA
[2] Tokushima Univ, Dept Surg, Tokushima 7791510, Japan
关键词
Lenvatinib; Curcumin; EGFR; hepatocellular carcinoma; PI3K-AKT; resistance; ATEZOLIZUMAB PLUS BEVACIZUMAB; 1ST-LINE TREATMENT; NON-INFERIORITY; SORAFENIB; EFFICACY; CANCER; SAFETY;
D O I
10.3390/cells12040612
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence suggests that epidermal growth factor receptor (EGFR) activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and that their combination has clinical application potential for adjunctive treatment in HCC.
引用
收藏
页数:16
相关论文
共 50 条
  • [31] APN-mediated phosphorylation of BCKDK promotes hepatocellular carcinoma metastasis and proliferation via the ERK signaling pathway
    Mengying Zhai
    Zixia Yang
    Chenrui Zhang
    Jinping Li
    Jing Jia
    Lingyi Zhou
    Rong Lu
    Zhi Yao
    Zheng Fu
    Cell Death & Disease, 11
  • [32] Curcumin inhibits oral squamous cell carcinoma proliferation and invasion via EGFR signaling pathways
    Zhen, Lei
    Fan, Desheng
    Yi, Xianghua
    Cao, Xinming
    Chen, Dong
    Wang, Liming
    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, 2014, 7 (10): : 6438 - 6446
  • [33] APN-mediated phosphorylation of BCKDK promotes hepatocellular carcinoma metastasis and proliferation via the ERK signaling pathway
    Zhai, Mengying
    Yang, Zixia
    Zhang, Chenrui
    Li, Jinping
    Jia, Jing
    Zhou, Lingyi
    Lu, Rong
    Yao, Zhi
    Fu, Zheng
    CELL DEATH & DISEASE, 2020, 11 (05)
  • [34] Synergistic antitumor efficacy of aspirin plus lenvatinib in hepatocellular carcinoma via regulating of diverse signaling pathways
    Yan, Xijing
    Yu, Haoyuan
    Liang, Jinliang
    Hu, Zhongying
    Li, Xuejiao
    Liu, Huanyi
    Yao, Jia
    Sui, Xin
    Zheng, Jun
    Li, Rong
    CELL DEATH DISCOVERY, 2023, 9 (01)
  • [35] Synergistic antitumor efficacy of aspirin plus lenvatinib in hepatocellular carcinoma via regulating of diverse signaling pathways
    Xijing Yan
    Haoyuan Yu
    Jinliang Liang
    Zhongying Hu
    Xuejiao Li
    Huanyi Liu
    Jia Yao
    Xin Sui
    Jun Zheng
    Rong Li
    Cell Death Discovery, 9
  • [36] Role of Thioredoxin Reductase 1 in Curcumin-mediated Radiosensitization of Oral Squamous Cell Carcinoma
    Hertan, L.
    Javvadi, P.
    Tuttle, S.
    Koumenis, C.
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2009, 75 (03): : S560 - S560
  • [37] Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma
    Zhou, He -Ming
    Chen, Da-Hong
    Diao, Wen-Jing
    Wu, Ya-Fei
    Zhang, Ji-Gang
    Zhong, Lin
    Jiang, Zhong-Yi
    Zhang, Xue
    Liu, Gao-Lin
    Li, Qin
    EXPERIMENTAL CELL RESEARCH, 2024, 436 (01)
  • [38] Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression
    Wang, Shuai
    Zhou, Lingyi
    Ji, Ning
    Sun, Chengtao
    Sun, Linlin
    Sun, Jiao
    Du, Yawei
    Zhang, Ningning
    Li, Yueguo
    Liu, Weishuai
    Lu, Wei
    DRUG RESISTANCE UPDATES, 2023, 69
  • [39] Identification of Fasudil as a collaborator to promote the anti-tumor effect of lenvatinib in hepatocellular carcinoma by inhibiting GLI2-mediated hedgehog signaling pathway
    Huang, Yilan
    Wang, Siwei
    Zhang, Xiaojun
    Yang, Chen
    Wang, Sikai
    Cheng, Hongxia
    Ke, Aiwu
    Gao, Chao
    Guo, Kun
    PHARMACOLOGICAL RESEARCH, 2024, 200
  • [40] Role of TGF-β signaling in curcumin-mediated inhibition of tumorigenicity of human lung cancer cells
    Datta, Raktima
    Halder, Sunil K.
    Zhang, Binhao
    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 2013, 139 (04) : 563 - 572