Erianthridin Induces Non-small Cell Lung Cancer Cell Apoptosis through the Suppression of Extracellular Signal-regulated Kinase Activity

Abstract

Due to the high mortality of lung cancer, natural derivative compounds have been promoted as versatile sources for anticancer drug discovery. Erianthridin, a phenanthrene compound isolated from Dendrobium formosum, exhibits intriguing apoptosis-inducing effects in non-small cell lung cancer cells. Apoptotic nuclei staining assays showed that apoptotic cells with DNA fragmentation and apoptotic bodies were apparent, and an increase in annexin V-FITC-positive cells were found in cells treated with erianthridin. The apoptosis protein markers for cleaved caspase-3 and cleaved poly-ADP-ribose polymerase were significantly upregulated in response to erianthridin. A mechanistic investigation revealed that erianthridin was able to attenuate extracellular signal-regulated kinase activity and thereby mediate apoptosis through the modulation of Bcl-2 family protein levels. U0126, an extracellular signal-regulated kinase inhibitor, augmented the apoptosis-inducing effect of erianthridin; in contrast, overexpression of exogenous extracellular signal-regulated kinase substantially abrogated erianthridin activity. Furthermore, an in vitro 3D tumorigenesis assay showed that erianthridin was able to potentially suppress lung cancer cell proliferation. This study is the first to report a promising cytotoxic effect of erianthridin, which provides preclinical evidence for further research and development of this compound.

Key words

apoptosis - Bcl-2 family proteins - Dendrobium densiflorum - erianthridin - extracellular signal-regulated kinase - Orchidaceae - non-small cell lung cancer cells

Publication History

Received: 04 August 2020

Accepted after revision: 17 October 2020

Article published online:
19 November 2020

• References

• 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68: 7-30
• 2 Tsvetkova E, Goss GD. Drug resistance and its significance for treatment decisions in non-small-cell lung cancer. Curr Oncol 2012; 19: S45
• 3 Sarin N, Engel F, Kalayda GV, Mannewitz M, Cinatl J, Rothweiler F, Michaelis M, Saafan H, Ritter CA, Jaehde U, Frötschl R. Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest. PLoS One 2017; 12: e0181081
• 4 OʼGrady S, Finn SP, Cuffe S, Richard DJ, OʼBryne KJ, Barr MP. The role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev 2014; 40: 1161-1170
• 5 Tannock IF, Hickman JA. Limits to personalized cancer medicine. N Engl J Med 2016; 13: 1289-1294
• 6 Bidarra SJ, Oliveira P, Rocha S, Saraiva DP, Oliveira C, Barrias CC. A 3D in vitro model to explore the inter-conversion between epithelial and mesenchymal states during EMT and its reversion. Sci Rep 2016; 6: 27072
• 7 Su Z, Yang Z, Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer 2015; 14: 48
• 8 Warren CFA, Wong-Brown MW, Bowden NA. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis 2019; 10: 177
• 9 Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HMCS, Signori E, Honoki K, Georgakilas AG, Amin A, Helferich WG, Boosani CS, Guha G, Ciriolo MR, Chen S, Mohammed SI, Azmi AS, Keith WN, Bilsland A, Bhakta D, Halicka D, Fujii H, Aquilano K, Ashraf S, Nowsheen S, Yang X, Choi BK, Kwon BS. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015; 35: S185-S198
• 10 Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013; 13: 714-726
• 11 Kowitdamrong A, Chanvorachote P, Sritularak B, Pongrakhananon V. Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. Biomed Res Int 2013; 2013: 1-11
• 12 Unahabhokha T, Chanvorachote P, Sritularak B, Kitsongsermthon J, Pongrakhananon V. Gigantol inhibits epithelial to mesenchymal process in human lung cancer cells. Evid Based Complement Alternat Med 2016; 2016: 1-10
• 13 Charoenrungruang S, Chanvorachote P, Sritularak B, Pongrakananon V. Gigantol-induced apoptosis in lung cancer cell through mitochondrial-dependent pathway. Thai J Pharm Sci 2014; 38: 67-73
• 14 Wattanathamsan O, Treesuwan S, Sritularak B, Pongrakananon V. Cypripedin, a phenanthrenequinone from Dendrobium densiflorum, sensitizes non-small cell lung cancer H460 cells to cisplatin-mediated apoptosis. J Nat Med 2018; 72: 1-11
• 15 Treesuwan S, Sritularak B, Chanvorachote P, Pongrakananon V. Cypripedin diminishes an epithelial-to-mesenchymal transition in non-small cell lung cancer cells through suppression of Akt/GSK-3β signalling. Sci Rep 2018; 8: 8009
• 16 Inthongkaew P, Chatsumpun N, Supasuteekul C, Kitisripanyac T, Putalunc W, Likhitwitayawuida K, Sritularaka B. α-Glucosidase and pancreatic lipase inhibitory activities and glucose uptake stimulatory effect of phenolic compounds from Dendrobium formosum. Rev Bras Farmacogn 2017; 27: 480-487
• 17 Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, Bao JK. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 2012; 45: 487-498
• 18 Adams JM, Cory S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ 2018; 25: 27-36
• 19 Delbridge ARD, Grabow S, Strasser A, Vaux DL. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 2016; 16: 99-109
• 20 Ha JH, Shin JS, Yoon MK, Lee MS, He F, Bae KH, Yoon HS, Lee CK, Park SG, Muto Y, Chi SW. Dual-site interactions of p53 protein transactivation domain with anti-apoptotic Bcl-2 family proteins reveal a highly convergent mechanism of divergent p53 pathways. J Biol Chem 2013; 288: 7387-7398
• 21 Liu ZH, Wang MH, Ren HJ, Qu W, Sun LM, Zhang QF, Qiu XS, Wang EH. Interleukin 7 signaling prevents apoptosis by regulating bcl-2 and bax via the p53 pathway in human non-small cell lung cancer cells. Int J Clin Exp Pathol 2014; 7: 870-881
• 22 Leroy B, Girard L, Hollestelle A, Minna JD, Gazdar AF, Soussi T. Analysis of TP53 mutation status in human cancer cell lines: a reassessment. Hum Mutat 2014; 35: 756-765
• 23 Burns TF, Dobromilskaya I, Murphy SC, Gajula RP, Thiyagarajan S, Chatley SNH, Aziz K, Cho YJ, Tran PT, Rudini CM. Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer. Mol Cancer Res 2013; 11: 329-338
• 24 Yang J, Kuang X, Lv P, Yan XX. Thymoquinone inhibits proliferation and invasion of human nonsmall-cell lung cancer cells via ERK pathway. Tumor Biol 2015; 36: 259-269
• 25 Chen M, Wang X, Zha D, Cai F, Zhang W, He Y, Huang Q, Zhuang H, Hua ZC. Apigenin potentiates TRAIL therapy of non-small cell lung cancer via upregulating DR4/DR5 expression in a p53-dependent manner. Nat Publ Gr 2016; 6: 35468
• 26 Shanker M, Willcutts D, Roth JA, Ramesh R. Drug resistance in lung cancer. Lung Cancer (Auckland, NZ) 2010; 1: 23-36
• 27 Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res 2017; 7: 1016-1036
• 28 Hassan M, Watari H, AbuAlmaaty A, Ohbe Y, Sakuragi N. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014; 2014: 150845
• 29 Mariño G, Kroemer G. Mechanisms of apoptotic phosphatidylserine exposure. Cell Res 2013; 23: 1247-1248
• 30 Hollville E, Martin SJ. Measuring apoptosis by microscopy and flow cytometry. Curr Protoc Immunol 2016; 112: 14.38.1-14.38.24
• 31 McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 2013; 5: a008656
• 32 Kuo CT, Chen BC, Yu CC, Weng CH, Hsu MJ, Chen CC, Chen MC, Teng CM, Pan SL, Bien MY, Shih CH, Lin CH. Apoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cells. J Biomed Sci 2009; 16: 43
• 33 Sánchez Duffhues G, Calzado MA, de Vinuesa AG, Appendino G, Fiebich BL, Loock U, Lefarth-Risse A, Krohn K, Muñoza E. Denbinobin inhibits nuclear factor-κB and induces apoptosis via reactive oxygen species generation in human leukemic cells. Biochem Pharmacol 2009; 77: 1401-1409
• 34 Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol 2018; 80: 50-64
• 35 Tóth B, Hohmann J, Vasas A. Phenanthrenes: a promising group of plant secondary metabolites. J Nat Prod 2018; 81: 661-678
• 36 Brahmbhatt H, Oppermann S, Osterlund EJ, Leber B, Andrews D. Molecular pathways: leveraging the BCL-2 interactome to kill cancer cells-mitochondrial outer membrane permeabilization and beyond. Clin Cancer Res 2015; 21: 2671-2676
• 37 Nakazawa K, Dashzeveg N, Yoshida K. Tumor suppressor p53 induces miR-1915 processing to inhibit Bcl-2 in the apoptotic response to DNA damage. FEBS J 2014; 281: 2937-2944
• 38 Fu X, Feng Y, Shao B, Zhang Y. Activation of the ERK/Creb/Bcl-2 pathway protects periodontal ligament stem cells against hydrogen peroxide-induced oxidative stress. Mol Med Rep 2019; 19: 3649-3657
• 39 Wu D, Wu T, Wu J, Cheng YW, Chen YC, Lee MC, Chen CY, Lee H. Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression. Oncogene 2014; 33: 4385-4395
• 40 Huang CC, Wu DW, Lin PL, Lee H. Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK-mediated stabilization of Bcl-2 protein by phosphorylation at Serine 87. Oncotarget 2015; 6: 8698-8708
• 41 Wang M, Lu X, Dong X, Hao F, Liu Z, Ni G, Chen D. pERK1/2 silencing sensitizes pancreatic cancer BXPC-3 cell to gemcitabine-induced apoptosis via regulating Bax and Bcl-2 expression. World J Surg Oncol 2015; 13: 66
• 42 Nunes AS, Barros AS, Costa EC, Moreira AF, Correia IJ. 3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugs. Biotechnol Bioeng 2019; 116: 206-226
• 43 Pongrakhananon V, Chunhacha P, Chanvorachote P. Ouabain suppresses the migratory behavior of lung cancer cells. PLoS One 2013; 8: e68623
• 44 Xu S, Yang Y, Dong L, Qiu W, Yang L, Wang X, Liua L. Construction and characteristics of an E-cadherin-related three-dimensional suspension growth model of ovarian cancer. Sci Rep 2015; 4: 5646
• 45 Li Q, Chow AB, Mattingly RR. Three-dimensional overlay culture models of human breast cancer reveal a critical sensitivity to mitogen-activated protein kinase kinase inhibitors. J Pharmacol Exp Ther 2010; 332: 821-828
• 46 Latcha S, Jaimes EA, Patil S, Glezerman IG, Mehta S, Flombaum CD. Long-term renal outcomes after cisplatin treatment. Clin J Am Soc Nephrol 2016; 11: 1173-1179
• 47 Witayateeraporn W, Arunrungvichian K, Pothongsrisit S, Doungchawee J, Vajragupta O, Pongrakhananon V. α7-Nicotinic acetylcholine receptor antagonist QND7 suppresses non-small cell lung cancer cell proliferation and migration via inhibition of Akt/mTOR signaling. Biochem Biophys Res Commun 2020; 521: 977-983
• 48 Pongrakhananon V, Wattanathamsan O, Takeichi M, Chetprayoon P, Chanvorachote P. Loss of CAMSAP3 promotes EMT via the modification of microtubule-Akt machinery. J Cell Sci 2018; 131: jcs216168