Methyleugenol enhances the anticancer effect of chemotherapeutic drug and boosts chemotherapy drug tolerance
Methyleugenol boosts chemotherapy drug tolerance
Abstract
Chemotherapy plays an important role in treating lung cancer. Chemotherapy drugs usually have good therapeutic effect, but due to the side effects, the dose needs to be considered. The use of non-toxic adjuvant natural product combined with chemotherapy drugs will be an important treatment mode in the future. The purpose of this study is to use non-toxic natural product (methyleugenol) to increase the therapeutic effect of chemotherapeutic agent (doxorubicin) on lung cancer and investigate the toxic effect of methyleugenol combined with chemotherapeutic agents on drug-resistant lung cancer cells. Methyleugenol combined with doxorubicin treated lung adenocarcinoma A549 cell line and established drug-resistant lung adenocarcinoma cell line (A549DoxR) were used in the study.
The methods including proliferation assay, cell wound healing assay, colony formation assay, DNA fragmentation assay, gelatin zymography assay, comet assay, reverse transcriptional polymerase chain reaction (RT-PCR), and western blot were adopted. The results showed methyleugenol significantly enhanced doxorubicin inhibited the cell growth, the cell colony formation, the cell migration, and the metastasis of A549 cells and A549DoxR cells. Methyleugenol strengthened doxorubicin to induce apoptosis and autophagy of A549 cells and A549DoxR cells. Methyleugenol can significantly enhance the treatment effect of chemotherapy drugs in lung cancer and strengthened the toxic effect of chemotherapy drugs on drug-resistant lung cancer cells. Methyleugenol can be developed to be used as an adjuvant to assist Chemotherapy drugs s and is targeted to clinically treat patients with multidrug resistance.
References
Booth LA, Tavallai S, Hamed HA, Cruickshanks N, Dent P. (2014). The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell Signal. 26(3):549-555.
Chaft JE, Rimner A, Weder W, Azzoli CG, Kris MG, Cascone T. (2021). Evolution of systemic therapy for stages I-III non-metastatic non-small-cell lung cancer. Nat Rev Clin Oncol. 18(9):547-557.
Che CT, Wang ZJ, Chow MS, Lam CW. (2013). Herb-herb combination for therapeutic enhancement and advancement: theory, practice and future perspectives. Molecules. 18(5):5125-5141.
Chen J, Khalil RA. (2017). Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia. Prog Mol Biol Transl Sci. 148:87-165.
Colotti G, Poser E, Fiorillo A, Genovese I, Chiarini V, Ilari A. (2014). Sorcin, a calcium binding protein involved in the multidrug resistance mechanisms in cancer cells. Molecules. 19(9): 13976-13989.
Ellis PM, Vella ET, Ung YC. (2017). Immune Checkpoint Inhibitors for Patients With Advanced Non-Small-Cell Lung Cancer: A Systematic Review. Clin Lung Cancer. 18(5):444-459
Fadejeva I, Olschewski H, Hrzenjak A. (2017). MicroRNAs as regulators of cisplatin-resistance in non-small cell lung carcinomas. Oncotarget. 8(70):115754-115773.
Gaffney J, Solomonov I, Zehorai E, Sagi I. (2015). Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo. Matrix Biol. 44-46:191-199.
Genovese I, Fiorillo A, Ilari A, Masciarelli S, Fazi F, Colotti G. (2017). Binding of doxorubicin to Sorcin impairs cell death and increases drug resistance in cancer cells. Cell Death Dis. 8(7): e2950.
Guo H, Liu JX, Li H, Baak JPA. (2017). In Metastatic Non-small cell Lung Cancer Platinum-Based Treated Patients, Herbal Treatment Improves the Quality of Life. A Prospective Randomized Controlled Clinical Trial. Front Pharmacol. 8:454.
Huang SF, Chu SC, Hsieh YH, Chen PN, Hsieh YS. (2018). Viola Yedoensis Suppresses Cell Invasion by Targeting the Protease and NF-kappaB Activities in A549 and Lewis Lung Carcinoma Cells. Int J Med Sci. 15(4):280-290.
Hamacher-Brady A, Brady NR, Gottlieb RA. (2006). Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem. 281(40):29776-29787.
He M, Zhou Z, Wu G, Chen Q, Wan Y. (2017). Emerging role of DUBs in tumor metastasis and apoptosis: Therapeutic implication. Pharmacol Ther. 177:96-107.
Hu Y, Li S, Yang M, Yan C, Fan D, Zhou Y, Xiong D. (2014). Sorcin silencing inhibits epithelial-to-mesenchymal transition and suppresses breast cancer metastasis in vivo. Breast Cancer Res Treat. 143(2):287-299.
Kebsa W, Lahouel M, Rouibah H, Zihlif M, Ahram M, Abu-Irmaileh B, Al Shhab M. (2018). Reversing Multidrug Resistance in Chemo-resistant Human Lung Adenocarcinoma (A549/DOX) Cells by Algerian Propolis Through Direct Inhibiting the P-gp Efflux-pump, G0/G1 Cell Cycle Arrest and Apoptosis Induction. Anticancer Agents Med Chem. 18(9): 1330-1337.
Khan I, Bahuguna A, Bhardwaj M, Pal Khaket T, Kang SC. (2018). Carvacrol nanoemulsion evokes cell cycle arrest, apoptosis induction and autophagy inhibition in doxorubicin resistant-A549 cell line. Artif Cells Nanomed Biotechnol. 46(sup1):664-675.
Li M, Zhai G, Gu X, Sun K. (2018). ATF3 and PRAP1 play important roles in cisplatin-induced damages in microvascular endothelial cells. Gene. 672:93-105.
Lin SR, Fu YS, Tsai MJ, Cheng H, Weng CF. (2017). Natural Compounds from Herbs that can Potentially Execute as Autophagy Inducers for Cancer Therapy. Int J Mol Sci. 18(7):1412.
Lu W, Kang Y. (2019). Epithelial-Mesenchymal Plasticity in Cancer Progression and Metastasis. Dev Cell. 49(3):361-374.
Osman AM, Bayoumi HM, Al-Harthi SE, Damanhouri ZA, Elshal MF. (2012). Modulation of doxorubicin cytotoxicity by resveratrol in a human breast cancer cell line. Cancer Cell Int. 12(1):47.
Parzych KR, Klionsky DJ. (2014). An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. 20(3):460-473.
Radogna F, Dicato M, Diederich M. (2015). Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. Biochem Pharmacol. 94(1):1-11.
Rahat B, Sharma R, Bagga R, Hamid A, Kaur J. (2016). Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases. Reproduction. 152(1):11-22.
Ribatti D, Tamma R, Annese T. (2020). Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl Oncol. 13(6):100773.
Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, Grothe A. (2018). 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 10:1758835918780140.
Siegel L, Miller KD , Fuchs HE, Jemal A. 2021. Cancer Statistics, (2021). CA Cancer J Clin. 71(1):7-33
Siegel RL, Miller KD, Jemal A. 2019. Cancer statistics, (2019). CA Cancer J Clin. 69(1):7-34.
Shabnam B, Padmavathi G, Banik K, Girisa S, Monisha J, Sethi G, Kunnumakkara AB. (2018). Sorcin a Potential Molecular Target for Cancer Therapy. Transl Oncol. 11(6):1379-1389.
Testa U, Castelli G, Pelosi E. (2018). Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers (Basel). 10(8):248.
Webb AH, Gao BT, Goldsmith ZK, Irvine AS, Saleh N, Lee RP, Lendermon JB, Bheemreddy R, Zhang Q, Brennan RC, Johnson D, Steinle J, Wilson MW, Morales-Tirado VM. (2017). Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer. 17(1):434.
Yan C, Boyd DD. (2006). ATF3 regulates the stability of p53: a link to cancer. Cell Cycle, 5(9):926-929.
Yu X, Mao J, Mahmoud S, Huang H, Zhang Q, Zhang J. (2018). Soluble resistance-related calcium-binding protein in cancers. Clin Chim Acta. 486:369-373.
