Anti-tumor Activity of Shikonin Against Afatinib Resistant Non-small Cell Lung Cancer Via Negative Regulation of PI3K/Akt Signaling Pathway

Overview

Journal Biosci Rep

Specialty Cell Biology

Date 2018 Nov 14

PMID 30420490

Citations 11

Authors

Baiying Li

Zuguo Yuan

Jin Jiang

Yuanquan Rao

Affiliations

Soon will be listed here.

Abstract

Acquired resistance of afatinib is a significant challenge for non-small cell lung cancer (NSCLC) therapy and the mechanisms remain unclear. Aberrant activation of epidermal growth factor receptor (EGFR)-dependent downstream pathways, especially phosphatidylinositol-3-kinases/protein kinase B (PI3K/Akt) signaling pathway has been reported to be involved in the occurrence of afatinib resistance. Developing effective anti-cancer agents to overcome afatinib resistance by targetting PI3K/Akt signaling pathway will be a potential strategy for NSCLC treatment. Shikonin is a naphthoquinone compound isolated from the roots of In the present study, the anti-cancer activity of Shikonin was evaluated on afatinib-resistant NSCLC and The data showed that Shikonin inhibited the proliferation and induced apoptosis of afatinib-resistant NSCLC cell line by activating apoptosis signaling pathway and negatively regulating PI3K/Akt signaling pathway. These results revealed that Shikonin was a potential apoptosis inducer in afatinib-resistant NSCLC and a promising candidate for treating patients clinically.

Citing Articles

Research progress in mechanism of anticancer action of shikonin targeting reactive oxygen species.

Qi K, Li J, Hu Y, Qiao Y, Mu Y Front Pharmacol. 2024; 15:1416781.

PMID: 39076592 PMC: 11284502. DOI: 10.3389/fphar.2024.1416781.

Attenuation of PI3K-Akt-mTOR Pathway to Reduce Cancer Stemness on Chemoresistant Lung Cancer Cells by Shikonin and Synergy with BEZ235 Inhibitor.

Huang Y, Chiu L, Tseng J, Hsu K, Chen C, Sheu G Int J Mol Sci. 2024; 25(1).

PMID: 38203787 PMC: 10779050. DOI: 10.3390/ijms25010616.

Shikonin Mediates Apoptosis through G Protein-Coupled Estrogen Receptor of Ovarian Cancer Cells.

Liu X, Yang Y, Tang X, Guo L, Tang X, Zhu T Evid Based Complement Alternat Med. 2022; 2022:6517732.

PMID: 36248433 PMC: 9556250. DOI: 10.1155/2022/6517732.

Recent Research Progress of Chiral Small Molecular Antitumor-Targeted Drugs Approved by the FDA From 2011 to 2019.

Chu X, Bu Y, Yang X Front Oncol. 2022; 11:785855.

PMID: 34976824 PMC: 8718447. DOI: 10.3389/fonc.2021.785855.

Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells.

Qi H, Zhang X, Liu H, Han M, Tang X, Qu S J Cancer. 2022; 13(1):243-252.

PMID: 34976186 PMC: 8692675. DOI: 10.7150/jca.65297.

References

Zhai T, Hei Z, Ma Q, Liang H, Xu Y, Zhang Y . Shikonin induces apoptosis and G0/G1 phase arrest of gallbladder cancer cells via the JNK signaling pathway. Oncol Rep. 2017; 38(6):3473-3480. DOI: 10.3892/or.2017.6038. View

Coco S, Truini A, Alama A, Dal Bello M, Vene R, Garuti A . Afatinib resistance in non-small cell lung cancer involves the PI3K/AKT and MAPK/ERK signalling pathways and epithelial-to-mesenchymal transition. Target Oncol. 2014; 10(3):393-404. DOI: 10.1007/s11523-014-0344-7. View

Wang H, Fei Z, Jiang H . Polyphyllin VII increases sensitivity to gefitinib by modulating the elevation of P21 in acquired gefitinib resistant non-small cell lung cancer. J Pharmacol Sci. 2017; 134(3):190-196. DOI: 10.1016/j.jphs.2017.06.005. View

Zhao P, Jiang H, Su D, Feng J, Ma S, Zhu X . Inhibition of cell proliferation by mild hyperthermia at 43˚C with Paris Saponin I in the lung adenocarcinoma cell line PC-9. Mol Med Rep. 2014; 11(1):327-32. DOI: 10.3892/mmr.2014.2655. View

Xie M, He J, He C, Wei S . γ Secretase inhibitor BMS-708163 reverses resistance to EGFR inhibitor via the PI3K/Akt pathway in lung cancer. J Cell Biochem. 2015; 116(6):1019-27. DOI: 10.1002/jcb.25056. View

Lu B, Gong X, Wang Z, Ding Y, Wang C, Luo T . Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation. Acta Pharmacol Sin. 2017; 38(11):1543-1553. PMC: 5672068. DOI: 10.1038/aps.2017.112. View

Zheng R, Jiang H, Li J, Liu X, Xu H . Polyphyllin II Restores Sensitization of the Resistance of PC-9/ZD Cells to Gefitinib by a Negative Regulation of the PI3K/Akt/mTOR Signaling Pathway. Curr Cancer Drug Targets. 2017; 17(4):376-385. DOI: 10.2174/1568009616666161213141608. View

Fang Z, Chen W, Yuan Z, Liu X, Jiang H . LncRNA-MALAT1 contributes to the cisplatin-resistance of lung cancer by upregulating MRP1 and MDR1 via STAT3 activation. Biomed Pharmacother. 2018; 101:536-542. DOI: 10.1016/j.biopha.2018.02.130. View

Li X, Fan X, Jiang Z, Loo W, Yao X, Leung E . Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway. Pharmacol Res. 2016; 115:45-55. DOI: 10.1016/j.phrs.2016.11.011. View

10.

Shahsavari Z, Karami-Tehrani F, Salami S . Targeting Cell Necroptosis and Apoptosis Induced by Shikonin via Receptor Interacting Protein Kinases in Estrogen Receptor Positive Breast Cancer Cell Line, MCF-7. Anticancer Agents Med Chem. 2017; 18(2):245-254. DOI: 10.2174/1871520617666170919164055. View

11.

Wu D, Wu T, Chen C, Lee H . PAK1 Is a Novel Therapeutic Target in Tyrosine Kinase Inhibitor-Resistant Lung Adenocarcinoma Activated by the PI3K/AKT Signaling Regardless of EGFR Mutation. Clin Cancer Res. 2016; 22(21):5370-5382. DOI: 10.1158/1078-0432.CCR-15-2724. View

12.

Ni F, Huang X, Chen Z, Qian W, Tong X . Shikonin exerts antitumor activity in Burkitt's lymphoma by inhibiting C-MYC and PI3K/AKT/mTOR pathway and acts synergistically with doxorubicin. Sci Rep. 2018; 8(1):3317. PMC: 5820316. DOI: 10.1038/s41598-018-21570-z. View

13.

Park K, Tan E, OByrne K, Zhang L, Boyer M, Mok T . Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016; 17(5):577-89. DOI: 10.1016/S1470-2045(16)30033-X. View

14.

Han J, Zhao F, Zhang J, Zhu H, Ma H, Li X . miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway. Int J Oncol. 2016; 48(5):1855-67. PMC: 4809653. DOI: 10.3892/ijo.2016.3401. View

15.

Lu D, Qian J, Li W, Feng Q, Pan S, Zhang S . β-hydroxyisovaleryl-shikonin induces human cervical cancer cell apoptosis via PI3K/AKT/mTOR signaling. Oncol Lett. 2016; 10(6):3434-3442. PMC: 4665374. DOI: 10.3892/ol.2015.3769. View

16.

Tang J, Zhao J, Long F, Chen J, Mu B, Jiang Z . Efficacy of Shikonin against Esophageal Cancer Cells and its possible mechanisms and . J Cancer. 2018; 9(1):32-40. PMC: 5743709. DOI: 10.7150/jca.21224. View

17.

Hsieh Y, Liao C, Chen W, Pai J, Weng M . Shikonin Inhibited Migration and Invasion of Human Lung Cancer Cells via Suppression of c-Met-Mediated Epithelial-to-Mesenchymal Transition. J Cell Biochem. 2017; 118(12):4639-4651. DOI: 10.1002/jcb.26128. View

18.

Yang Q, Chen W, Xu Y, Lv X, Zhang M, Jiang H . Polyphyllin I modulates MALAT1/STAT3 signaling to induce apoptosis in gefitinib-resistant non-small cell lung cancer. Toxicol Appl Pharmacol. 2018; 356:1-7. DOI: 10.1016/j.taap.2018.07.031. View

19.

Sharma A, Shepard J . Lung Cancer Biopsies. Radiol Clin North Am. 2018; 56(3):377-390. DOI: 10.1016/j.rcl.2018.01.001. View

20.

Song S, Du L, Jiang H, Zhu X, Li J, Xu J . Paris Saponin I Sensitizes Gastric Cancer Cell Lines to Cisplatin via Cell Cycle Arrest and Apoptosis. Med Sci Monit. 2016; 22:3798-3803. PMC: 5081239. DOI: 10.12659/msm.898232. View