Cancer Stem Cells, the Cellular Signaling, and Potential Therapeutic Targets in Lung Cancer

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Published: Jun 8, 2021
Keywords:
cancer stem cells CSC-targeting therapy cell signaling drug target lung cancer

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Nattamon Hongwiangchan
Graduate Program of Pharmaceutical Science and Technology, Faculty of Pharmaceutical Science, Chulalongkorn University, Bangkok, Thailand
Pithi Chanvorachote
Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
Sucharat Tungsukruthai
Doctor of Philosophy Program in Interdisciplinary Pharmacology, Graduate School, Chulalongkorn University, Bangkok, Thailand

Abstract

Recent studies in the field of cancer cell biology have pointed out that the cancer cells having stem cell property in tumor may contribute aggressive phenotypes of cancers. A limited population of cancer cells exhibiting high ability to generate new tumor named “cancer stem cells (CSCs)” has garnered significant attention in these years and was linked with the initiation of primary tumor and cancer cells as well as the successful establishment of metastatic tumors. Based on the theory that stem cells preserve their ability to generate the new clones with different cell lineages because of their pluripotency, CSCs similarly exert its tumorigenicity. Besides, CSCs were shown to highly resist to currently used anticancer drugs and have augmented ability to metastasis. It is worthy highlighted that the CSCs that survive after chemotherapeutic treatment are believed to be the cause of disease relapse. Taken together, these evidences have supported the development of CSC-based targeted therapy. This review aimed at describing the fundamental information regarding the role of CSCs in lung cancer and its cellular signaling that may benefit the understanding and support the development of CSC-targeting research.

Article Details

Issue
Vol. 43 No. 1 (2021): Thai Journal of Pharmacology
Section
Review Articles

Upon acceptance of an article, the Pharmacological and Therapeutic Society of Thailand will have exclusive right to publish and distribute the article in all forms and media and grant rights to others. Authors have rights to use and share their own published articles.

Author Biography

Pithi Chanvorachote, Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand

Research Publications
  1. Pithi Chanvorachote, Ubonthip Nimmannit, Liying Wang, Christian Stehlik, Bin Lu, Neelam Azad, and Yon Rojanasakul*. Nitric Oxide Negatively Regulates Fas CD95-induced Apoptosis through Inhibition of Ubiquitin-Proteasome-mediated Degradation of FLICE Inhibitory Protein. Journal of Biological Chemistry. (2005); 280: 42044-42050.
  2. Pithi Chanvorachote, Ubonthip Nimmannit, Christian Stehlik, Liying Wang,  Boonsri Ongpipatanakul,   and Yon Rojanasakul*.  Nitric Oxide Regulates Cell Sensitivity to Cisplatin-Induced Apoptosis through  S-nitrosylation and Inhibition of Bcl-2 Ubiquitination, Cancer Research. (2006); 66:6353-6360.
  3. Pithi Chanvorachote*, Ubonthip Nimmannit, Yongju Lu, Siera Talbott, Bing-Hua Jiang, and Yon Rojanasakul*. Nitric Oxide Regulates Lung Carcinoma Cell Anoikis through Inhibition of Ubiquitin-Proteasomal Degradation of Caveolin-1. Journal of Biological Chemistry. (2009); 284: 28476-28484.  
  4. Varisa Pongrakhananon, Ubonthip Nimmannit, Sudjit Luanpitpong, Yon Rojanasakul, and Pithi Chanvorachote*. Curcumin sensitizes non-small cell lung cancer cell anoikis through reactive oxygen species-mediated Bcl-2 downregulation. Apoptosis. (2010); 15:574–585
  5. Sudjit Luanpitpong, Siera Jo Talbott, Yon Rojanasakul, Ubonthip Nimmannit, Varisa Pongrakhananon, Liying Wang, and Pithi Chanvorachote*. Regulation of lung cancer cell migration and invasion by reactive oxygen species and Caveolin-1. Journal of Biological Chemistry.(2010); 285(50) : 38832- 38840.  
  6. Pithi Chanvorachote and Varisa Pongrakhananon*. Ouabain down-regulates Mcl-1 and sensitizes TRAIL-induced apoptosis in lung cancer cells. American Journal of Physiology-Cell Physiology. (2013); 304( 3): 263-272.
  7. Jirapan Muangjareon, Ubonthip Nimmannit, Patrick S Callery, Liying Wang, Neelam Azad, Vimolmas Lipipun, Pithi Chanvorachote and Yon Rojanasakul*. Reactive Oxygen species Mediate Caspase Activation and Apoptosis Induced by Lipoic Acid in Human Lung Epithelial Cancer Cells through Bcl-2 Downregulation. Journal of pharmacology and experimental therapeutics. (2006); 319 (3). 1062-1069.
  8. Liying Wang, Pithi Chanvorachote, David Toledo, Christian Stehlik, Robert R. Mercer, Vincent Castranova, and Yon Rojanasakul*. Peroxide is a key mediator of Bcl-2 down-regulation and apoptosis induction by cisplatin in human lung cancer cells. Molecular Pharmacology (2007); 73(1): 119-127. 
  9. Sumalee Wannachaiyasit, Pithi  Chanvorachote, and Ubonthip Nimmannit*. A Novel Anti-HIV Dextrin-Zidovudine Conjugate Improving the Pharmacokinetics of Zidovudine in Rats. AAPS PharmSci Tech. (2008); 9(3): 840-850.
  10. Pithi Chanvorachote*, Varisa Pongrakhananon, Sumalee Wannachaiyasit, Sudjit Luanpitpong, Yon Rojanasakul, Ubonthip Nimmannit. Curcumin sensitized lung cancer cells to cisplatin-induced apoptosis through superoxide anion induction and Bcl-1 degradation. Cancer Investigation. (2009); 27(6) : 624 – 635.
  11. Sudjit Luanpitpong, Varisa Pongrakhananon, Ubonthip Nimmannit, and Pithi Chanvorachote*. Emblica extract prevents cisplatin-induced apoptosis in dermal papilla fibroblasts. Songklanakarin Journal of Science and Technology. (2008); 30(5) : 627-633.
  12. Pithi Chanvorachote*, Varisa Pongrakhananon, Sudjit Luanpitpong, Boontarika Chanvorachote, Sumalee Wannachaiyasit, and Ubonthip Nimmannit*. Type I Pro-collagen Promoting and Anti-collagenase Activities of Phyllanthus emblica Extract in Mouse Fibroblast. Journal of Cosmetic Science. (2009); 60 : 395-403.
  13. Boonchu Sritularak, Aungkana Tantituvanont, Pithi Chanvorachote, Kulwara Meksawan, Tomofumi Miyamoto, Yuhki Kohno, and Kitisak Likhitwitayawuid. Flavonoids with free radical scavenging activity and nitric oxide inhibitory effect from the stem bark of Artocarpus gomezianus. Journal of Medicinal Plant Research. (2010); 4(5): 387-392.
  14. Sudjit Luanpitpong, Ubonthip Nimmannit, Varisa Pongrakhananon, and Pithi Chanvorachote*. Emblica (Phyllanthus emblica Linn.) Fruit Extract Promotes Proliferation in Dermal Papilla Cells of Human Hair Follicle. Journal of Medicinal Plants Research.(2011); 5(1):95-100
  15. Hasseri Halim, Preedakorn Chunhacha, Khanit Suwanborirux, and Pithi Chanvorachote*. Anti-cancer and antimetastatic activities of renieramycin M, a marine tetrahydroisoquinoline alkaloid, in human non-small cell lung cancer cells.  Anticancer Res. (2011); 31: 193-201.
  16. Pimuma Rungtabnapa, Ubonthip Nimmannit, Hasseri Halim, Yon Rojanasakul, and Pithi Chanvorachote*. Hydrogen peroxide inhibits non-small cell lung cancer cell anoikis through the inhibition of caveolin-1 degradation. American Journal of Physiology-Cell Physiology.(2011) ;  300 : C235-C245.
  17. Kanittha Pongjit, Chaunpit Ninsontia, Chatchai Chaotham, and Pithi Chanvorachote*. Protective Effect of Glycine max and Chrysanthemum indicum Extracts Against Cisplatin-Induced Renal Epithelial Cell Death. Human & Experimental Toxicology. (2011); 30(12):1931-44.
  18. Chuanpit Ninsontia, Kanittha Pongjit, Chatchai Chaotham, and Pithi Chanvorachote*. Silymarin selectively protects human renal cells from cisplatin-induced cell death. Pharmaceutical Biology. (2011); 49(10):1082-90.
  19. Sudjit Luanpitpong, Ubonthip Nimmannit, Pithi Chanvorachote, Stephen S. Leonard, Varisa Pongrakhananon, Liying Wang, and Yon Rojanasakul. Hydroxyl radical mediates cisplatin-induced apoptosis in human hair follicle dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism. Apoptosis. (2011) 16(8):769-82.
  20. Kanittha Pongjit and Pithi Chanvorachote*. Caveolin-1 sensitizes cisplatin-induced lung cancer cell apoptosis via superoxide anion-dependent mechanism. Molecular and Cellular Biochemistry. (2011); 358(1-2):365-73.
  21. Supim Wongtongtair, Pithi Chanvorachote, Pilaiwanwadee Hutamekalin, Chaiyo Chaichantipyuth, Vimolmas Lipipun, Pornthep Tiensiwakul, and Duangdeun Meksuriyen. Barakol-induced apoptosis in P19 cells through generation of reactive oxygen species and activation of caspase-9. Journal of ethnopharmacology. (2011); 137(2):971-8.
  22. Buntitabhon Sirichanchuen, Thitima Pengsuparp*, and Pithi Chanvorachote*. Long-term cisplatin exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells. Molecular and cellular biochemistry. (2012); 364: 11-18.
  23. Wongsakorn Suchaoin and Pithi Chanvorachote*. Caveolin-1 Attenuates Hydrogen Peroxide-Induced Oxidative Damage to Lung Carcinoma Cells. Anticancer Research. (2012); 32 (2): 483-490
  24. Preedakorn Chunhacha, Varisa Pongrakhananon, Yon Rojanasakul, and Pithi Chanvorachote*. Caveolin-1 Regulates Mcl-1 Stability and Anoikis in Lung Carcinoma Cells. American Journal of Physiology-Cell Physiology. (2012) ; 302: C1284–C1292.
  25. Pithi Chanvorachote*, Sudjit Luanpitpong, Preedakorn Chunhacha, Worrawat Promden, and Virote Sriuranpong. Expression of CA125 and cisplatin susceptibility of pleural effusion-derived human lung cancer cells of a Thai patient. Oncology letters.(2012); 4: 252-256.   
  26. Thitiporn Songserm, Varisa Pongrakhananon, and Pithi Chanvorachote*. Sub-toxic cisapltin mediates anoikis resistance through hydrogen peroxide-induced Caveolin-1 up-regulation in non-small cell lung cancer cells. Anticancer research. (2012); 32(5): 1659-1669.
  27. Sudjit Luanpitpong, Pithi Chanvorachote, Ubonthip Nimmannit, Stephen S Leonard, Christian Stehlik, Liying Wang, Yon Rojanasakul*. Mitochondrial superoxide mediates doxorubicin-induced keratinocyte apoptosis through oxidative modification of ERK and Bcl-2 ubiquitination. Biochemical pharmacology. (2012); 83(12): 1643-54.           
  28. Hasseri Halim, Sudjit Luanpitpong, Pithi Chanvorachote*. Acquisition of anoikis Resistance up-regulates caveolin-1 expression in human non-small cell lung cancer Cells. Anticancer research. (2012); 32 : 1649- 1658.
  29. Chatchai Chaotham, Wanchai De-Eknamkul, and Pithi Chanvorachote*.  Protective effect of plaunotol against doxorubicin-induced renal cell death. Journal of Natural Medicines. (2012); 67(2):311-319.
  30. Preedakorn Chunhacha and Pithi Chanvorachote*. Roles of Caveolin-1 on anoikis resistance in Non Small Cell Lung Cancer. International Journal of Physiology, Pathophysiology and Pharmacology. (2012); 4(3):149-155.
  31. Hasseri Halim and Pithi Chanvorachote*. Long-term hydrogen peroxide exposure potentiates anoikis resistance and anchorage-independent growth in lung carcinoma cells. Cell Biology International. (2012); 36: 1055–1066.
  32. Apiriya Dhumrongvaraporn and Pithi Chanvorachote*. Kinetics of Ultraviolet B Irradiation-Mediated Reactive Oxygen Species Generation in Human Keratinocytes. Journal of Cosmetic Science. (2013); 64: 1-11.
  33. Kanuengnit Choochuay, Preedakorn Chunhacha, Varisa Pongrakhananon, Rataya Luechapudiporn, and Pithi Chanvorachote*. Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. Journal of Natural Medicines. (2012) 67(3):599-606
  34. Porntipa Chairuangkitti, Somsong Lawanprasert, Sittiruk Roytrakul, Sasitorn Aueviriyavit, Duangkamol Phummiratch, Kornphimol Kulthong, Pithi Chanvorachote, and Rawiwan Maniratanachote. Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS-independent pathways. Toxicology in Vitro. (2013); 27(1):330-8.
  35. Ekkarat Wongpankam, Preedakorn Chunhacha, Varisa Pongrakhananon, Boonchoo Sritulalak, and Pithi Chanvorachote*. Artonin E Mediates MCL1 Down-regulation and Sensitizes Lung Cancer Cells to Anoikis. Anticancer Research. (2013); 32: 5345-5352
  36. Preedakorn Chunhacha,Virote Sriuranpong, and Pithi Chanvorachote. Epithelial-mesenchymal transition mediates anoikis resistance and enhances invasion in pleural effusion-derived human lung cancer cells of a Thai patient. Oncology Letters. (2013): 5: 1043-1047.
  37. Phattrakorn Powan, Naoki Saito, Khanit Suwanborirux, and Pithi Chanvorachote*. Ecteinascidin 770, A Tetrahydroisoquinoline Alkaloid, Sensitizes Human Lung Cancer Cells to Anoikis. Anticancer Research. (2013). 33:505-512.          
  38. Pithi Chanvorachote, Akkarawut Kowitdamrong , Thidarat Ruanghirun, , Boonchoo Sritularak*, Chutichot Mungmee and Kittisak Likhitwitayawuid. Anti-metastatic activities of Bibenzyls from Dendrobium pulchellum. Natural Product Communications. (2013); 8(1):115-8
  39. Sudjit Luanpitpong, Pithi Chanvorachote, Christian Stehlik, William Wei Ning Tse, Patrick S Callery, Liying Wang, Yon Rojanasakul. Regulation of Apoptosis by Bcl-2 Cysteine Oxidation in Human Lung Epithelial Cells. Molecular Biology of the Cell. (2013); 24(6):858-69.
  40. Pithi Chanvorachote and Preedakorn Chunhacha*. Caveolin-1 regulates endothelial adhesion of lung cancer cells via reactive oxygen species-dependent mechanism. Plos One. (2013) 8(2) : e57466
  41. Akkarawut Kowitdamrong, Pithi Chanvorachote*, Boonchoo Sritularak and Varisa Pongrakhananon. Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. Biomed Research International. In press.
  42. Pithi Chanvorachote*, Preedakorn Chunhacha, and Varisa Pongrakhananon. Editorial: Anoikis: a potential target to prevent lung cancer metastasis. Lung cancer manage. (2013) 2(3):169-171.
  43. Kanok Plaibua, Varisa Pongrakhananon, Preedakorn Chunhacha, Boonchoo Sritularak, and Pithi Chanvorachote*. Effects of Artonin E on Migration and Invasion Capabilities of Human Lung Cancer Cells. Anticancer Research. (2013) 33: 3079-3088.
  44. Varisa Pongrakhananon, Preedakorn Chunhacha, and Pithi Chanvorachote* Ouabain suppresses migratory behavior of lung cancer cells. PLOS ONE. (2013) 8(7): e68623. 
  45. Arpasinee Sanuphan, Preedakorn Chunhacha, Varisa Pongrakhananon, and Pithi Chanvorachote*. Long-Term Nitric Oxide Exposure Enhances Lung Cancer Cell Migration. Biomed Research International. 2013;2013:186972. doi: 10.1155/2013/186972
  46. Thaniwan Cheun-Arom, Pithi Chanvorachote*, Natchanun Sirimangkalakitti, Taksina Chuanasa, Naoki Saito, Ikuro Abe, and Khanit Suwanborirux. Replacement of Quinone by 5-O-Acetylhydroquinone Abolishes Accidental Necrosis Inducing Effect while Preserving Apoptosis-Inducing Effect of Renieramycin M on Lung Cancer Cells. (2013). Journal of Natural Products. 76(8):1468-74.
  47. Oraphan Wanakhachornkrai, Varisa Pongrakhananon, Preedakorn Chunhacha, Aree Wanasuntronwong, Anusara Vattanajun, Boonyong Tantisira, Pithi Chanvorachote* and Mayuree H Tantisira*. Neuritogenic effect of standardized extract of Centella asiatica ECa233 on human neuroblastoma cells. BMC Complementary and Alternative Medicine 2013, 13:204.
  48. Varisa Pongrakhananon, Todd A Stueckle, Hua-Yu Leo Wang, George A O'Doherty, Cerasela Zoica Dinu, Pithi Chanvorachote, Yon Rojanasakul Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation. Biochemical pharmacology. In press
  49. Kulwara Meksawan, Urairut Sermsri, and Pithi Chanvorachote*. Zinc Supplementation Improves Anticancer Activity of Monocytes in Type 2 Diabetic Patients with Metabolic Syndrome. Anticancer Research. In press.
  50. Piyaparisorn Wongvaranon, Varisa Pongrakhananon, Preedakorn Chunhacha, and Pithi Chanvorachote*. Acquired Chemotherapeutic Resistance in Lung Cancer Cells Mediated by Prolonged Nitric Oxide Exposure. Anticancer Research. 2013 ;33(12):5433-44.
  51. Piyaparisorn Wongvaranon, Varisa Pongrakhananon and Pithi Chanvorachote*. Molecular mechanisms of chemotherapeutic resistance in lung cancer. Thai journal of Pharmaceutical Sciences 2014, 38 (1): 1-4.
  52. Chatchai Chaotham,Varisa Pongrakhananon, Boonchoo Sritularak, and Pithi Chanvorachote*. A Bibenzyl from Dendrobium ellipsophyllum inhibits epithelial to Mesenchymal Transition and Sensitizes Lung Cancer Cells to Anoikis. Anticancer Research 2014, 34: 1931-1938.
  53. Thidarat ruanghirun, Varisa Pongrakhananon, and Pithi Chanvorachote*. Ouabain Enhances Lung Cancer Cell Detachment. Anticancer Research, 2014 May;34(5):2231-8. 
  54. Phattrakorn Powan, Pithi Chanvorachote*. Nitric oxide mediates cell aggregation and mesenchymal to epithelial transition in anoikis-resistant lung cancer cells. Mol Cell Biochem. In press. DOI 10.1007/s11010-014-2066-7
  55. Thitita Unahabhokha , Apirada Sucontphunt, Ubonthip Nimmannit, Pithi Chanvorachote, Nuttida Yongsangguanchai, Varisa Pongrakhananon*. Molecular signaling in Keloid disease and current therapeutic approaches from natural based compounds. Pharmaceutical Biology. In press
  56. Pithi Chanvorachote*, Varisa Pongrakhananon, and Preedakorn Chunhacha*. Prolonged Nitric Oxide Exposure Enhances enhanced anoikis resistance and migration through Epithelial-Mesenchymal Transition and Caveolin-1 Up-regulation. Biomed Research International. In press
  57. Sopinya Charoenrungruang, Pithi Chanvorachote, Boonchoo Sritularak, and Varisa Pongrakhananon*. Gigantol, a Bibenzyl from Dendrobium draconis, Inhibits the Migratory Behavior of Non-Small-Cell Lung Cancer Cells. Journal of Natural Products. In press.
  58. Pithi Chanvorachote, Varisa Pongrakhananon*, and Preedakorn Chunhacha*. Caveolin-1 induces lamellipodia formation via an Akt-dependent pathway. Cancer Cell International 2014, 14:52.
  59. Sopanya Charoenrungruang, Pithi Chanvorachote, Boonchoo Sritularak, and Varisa Pongrakhananon*. Gigantol-induced apoptosis in lung cancer cell through mitochondrial-dependent pathway.  Thai journal of Pharmaceutical Sciences 2014, 38 (2): 67-73.
  60. Boonchoo Sritularak, Angkana Tantituvanont1, Pithi Chanvorachote, Kulwara Meksawan, T. Miyamoto, Y. Kohno, and Kitisak Likhitwitayawuid. Flavonoids with free radical scavenging activity and nitric oxide inhibitory effect from the stem bark of Artocarpus gomezianus. Journal of Medicinal Plants Research 4(5): 387-392.
  61. Vititda Awaiwanont, Angkana Tantituvanont*, Waraporn Suwakul, Kulwara Meksawan, and Pithi Chanvorachote*. Scavenging Activity of Whey Protein Hydrolysates in HaCaT Cells. Chiang Mai Journal of Science. In press.
  62. Chuanpit Ninsontia and Pithi Chanvorachote*.Ouabain Mediates Integrin Switch in Human Lung Cancer Cells. Anticancer research. 34(10):5495-502.
  63. Arnatchai Maiuthed and Pithi Chanvorachote*. Cisplatin at Sub-toxic Levels Mediates Integrin Switch in Lung Cancer Cells. Anticancer research. In press.
  64. Premkamol Pengpang, Boonchoo Sritularak, and Pithi Chanvorachote*. Dendrofalconerol A Suppresses Migrating Cancer Cells via EMT and Integrin Proteins. Anticancer research. In press.
  65. Thidarat Winitthana, Somsong Lawanprasert, Pithi Chanvorachote*. Triclosan potentiates epithelial-to-mesenchymal transition in anoikis-resistant human lung cancer cells. Plos One.  October 16, 2014, DOI: 10.1371/journal.pone.0110851
  66. Kasinee Tanagornmeatar, Chatchai Chaotham, Boonchoo Sritularak, Kitisak Likhitwitayawuid and Pithi Chanvorachote. Cytotoxic and Anti-metastatic Activities of Phenolic Compounds from Dendrobium ellipsophyllum. Anticancer Research. In press.
  67. Pithi Chanvorachote, Varisa Pongrakhananon, and Hasseri Halim. Caveolin-1 Regulates Metastatic Behaviors of Anoikis Resistant Lung Cancer Cells. Molecular and Cellular Biochemistry. In press.
  68. Premkamol Pengpang, Boonchoo Sritularak, Pithi Chanvorachote. Dendrofalconerol A sensitizes anoikis and inhibits migration in lung cancer cells. Journal of Natural Medicines. In press. 
  69. Nuttida Yongsanguanchai, Varisa Pongrakhananon, Apiwat Mutirangura, Yon Rojanasakul, and Pithi Chanvorachote*. Nitric Oxide induces Cancer Stem Cell-like Phenotypes in Human Lung Cancer Cells. American Journal of Physiology-Cell Physiology. In press.
  70. Sukhontha Hasatsri, Rungnapha Yamdech, Pithi Chanvorachote, and Pornanong Aramwit*. Physical and biological assessments of the innovative bilayered wound dressing made of silk and gelatin for clinical applications. Journal of  Biomaterials Applications. 2014 Nov 12. pii: 0885328214559138. In press.
  71. Tanagornmeatar K, Chaotham C, Sritularak B, Likhitwitayawuid K, Chanvorachote P. Cytotoxic and Anti-metastatic Activities of Phenolic Compounds from Dendrobium ellipsophyllum. Anticancer research. In press.

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