卵巢癌不容易被治癒的原因為其難以被早期察覺，以及其容易對化療藥物產生抗藥性，儘管現今已開發出許多新型抗癌療法，例如:標靶藥物、免疫療法及精準醫療，化療抗藥性的產生依舊是需要被關心的議題，因為化療仍舊廣泛應用於癌症病患中，也因此找尋潛在、針對化療抗藥性的結合治療是迫切的。至目前為止，許多科學家針對人體中的大麻素系統來治療癌症，其中有研究指出內生性大麻素具有抗腫瘤作用，但其是否可以在卵巢癌中降低化療抗藥性仍是未知。在此研究中，我們結合內生性大麻素，如:花生四烯乙醇胺及2-花生四烯酰甘油，與化療藥物一同作為治療卵巢癌的方法。本研究使用非抗藥及抗藥性ES2及IGROV1卵巢癌細胞株，以檢驗結合治療於不同型態之卵巢癌有治療效果。實驗使用生物資訊及分子技術探討內生性大麻素是否可以降低抗藥性，同時探討內生性大麻素結合化療藥物後是否能夠引發細胞凋亡。研究發現結合內生性大麻素及化療藥物 – 順鉑或太平洋紫杉醇可以抑制抗藥性卵巢癌細胞之細胞生長，同時我們發現當與單獨使用化療藥物比較時，結合性治療可以在抗藥性細胞中引發最高達40倍的細胞凋亡。其機制為內生性大麻素透過上調神經醯胺增加內質網壓力，並活化下游的細胞自噬，使用多球殼菌素抑制神經醯胺的生成，可以減緩內質網壓力及降低細胞自噬程度。根據細胞實驗結果，我們的研究展示內生性大麻素可以透過增加細胞自噬程度以克服卵巢癌之抗藥性的可能性，使內生性大麻素具有於化療藥物中作為佐劑的潛力。

Ovarian cancer (OVC) is challenging to cure due to its difficulty in early detection and its tendency to develop resistance to chemotherapy. While various innovative cancer treatments, such as targeted therapies, immunotherapies, and precision medicine, have emerged in recent years, concerns persist about chemoresistance. This is because chemotherapy remains the prevailing treatment option for most cancer patients. Hence, there is a pressing need to explore potential combination treatments for OVC. So far, there have been several research targeting the endocannabinoid system (ECS) in cancer. Among the different cannabinoid-based drugs, endocannabinoids have demonstrated several anti-tumor effects. However, research exploring their potential to combat chemoresistance in OVC is still inconclusive. In this study, endocannabinoids, namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), were combined with chemotherapy as an innovative approach for treating OVC. We employed two distinct ovarian cancer cell lines, ES2 and IGROV1, along with their chemoresistant counterparts, to ensure that the therapeutic effects could be observed across various OVC types. Bioinformatics and molecular approaches were used to examine whether endocannabinoids reduce chemoresistance and induce apoptosis in combination with chemotherapy. Our findings indicated a significant inhibition of cancer cell growth, with up to a 40-fold increase in cell apoptosis when endocannabinoids were combined with chemotherapeutic drugs (cisplatin or paclitaxel), in comparison to chemotherapy alone, in chemoresistant cancer cells. The subsequent results demonstrated that the increase in ceramide levels triggered by endocannabinoids resulted in the activation of endoplasmic reticulum (ER) stress pathways and the enhancement of autophagy. Reducing ceramide production with myriocin mitigated ER stress and autophagy levels. Our study has shown that endocannabinoids have the potential to combat chemoresistance in OVC in vitro by inducing autophagy, implying their potential use as complementary treatments alongside chemotherapy.

1. Siegel RL, Miller KD, Wagle NS and Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023; 73: 17-48.
2. Teng YH, Liu FC, Huang SY, Kuo CF and Yu HP. Epidemiology and mortality of ovarian cancer in taiwan: A population-based study. J Clin Med 2022; 11: 5627.
3. Maleki Z, Vali M, Nikbakht HA, Hassanipour S, Kouhi A, Sedighi S, Farokhi R and Ghaem H. Survival rate of ovarian cancer in Asian countries: a systematic review and meta-analysis. BMC Cancer 2023; 23: 558.
4. Roett MA and Evans P. Ovarian cancer: an overview. Am Fam Physician 2009; 80: 609-16.
5. Shih IM, Wang Y and Wang TL. The origin of ovarian cancer species and precancerous landscape. Am J Pathol 2021; 191: 26-39.
6. Karnezis AN, Cho KR, Gilks CB, Pearce CL and Huntsman DG. The disparate origins of ovarian cancers: pathogenesis and prevention strategies. Nat Rev Cancer 2017; 17: 65-74.
7. Kurman RJ and Shih IeM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34: 433-43.
8. Gaitskell K, Green J, Pirie K, Reeves G and Beral V. Tubal ligation and ovarian cancer risk in a large cohort: Substantial variation by histological type. Int J Cancer 2016; 138: 1076-84.
9. Sieh W, Salvador S, McGuire V, Weber RP, Terry KL, Rossing MA, Risch H, Wu AH, Webb PM, Moysich K, Doherty JA, Felberg A, Miller D, Jordan SJ, Goodman MT, Lurie G, Chang-Claude J, Rudolph A, Kjær SK, Jensen A, Høgdall E, Bandera EV, Olson SH, King MG, Rodriguez-Rodriguez L, Kiemeney LA, Marees T, Massuger LF, van Altena AM, Ness RB, Cramer DW, Pike MC, Pearce CL, Berchuck A, Schildkraut JM and Whittemore AS. Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies. Int J Epidemiol 2013; 42: 579-89.
10. Seidman JD and Khedmati F. Exploring the histogenesis of ovarian mucinous and transitional cell (Brenner) neoplasms and their relationship with Walthard cell nests: a study of 120 tumors. Arch Pathol Lab Med 2008; 132: 1753-60.
11. Domcke S, Sinha R, Levine DA, Sander C and Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun 2013; 4: 2126.
12. Beaufort CM, Helmijr JC, Piskorz AM, Hoogstraat M, Ruigrok-Ritstier K, Besselink N, Murtaza M, van IJcken WF, Heine AA, Smid M, Koudijs MJ, Brenton JD, Berns EM and Helleman J. Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. PLoS One 2014; 9: e103988.
13. Kuroki L and Guntupalli SR. Treatment of epithelial ovarian cancer. BMJ 2020; 371: m3773.
14. Lheureux S, Braunstein M and Oza AM. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA Cancer J Clin 2019; 69: 280-304.
15. Morand S, Devanaboyina M, Staats H, Stanbery L and Nemunaitis J. Ovarian cancer immunotherapy and personalized medicine. Int J Mol Sci 2021; 22: 6532.
16. Shaik B, Zafar T, Balasubramanian K and Gupta SP. An overview of ovarian cancer: molecular processes involved and development of target-based chemotherapeutics. Curr Top Med Chem 2021; 21: 329-46.
17. Guo C, Song C, Zhang J, Gao Y, Qi Y, Zhao Z and Yuan C. Revisiting chemoresistance in ovarian cancer: Mechanism, biomarkers, and precision medicine. Genes Dis 2020; 9: 668-681.
18. Ortiz M, Wabel E, Mitchell K and Horibata S. Mechanisms of chemotherapy resistance in ovarian cancer. Cancer Drug Resist 2022; 5: 304-16.
19. Kampan NC, Madondo MT, McNally OM, Quinn M and Plebanski M. Paclitaxel and is evolving role in the management of ovarian cancer. Biomed Res Int 2015; 2015: 413076.
20. Yang Y, Yang Y, Yang J, Zhao X and Wei X. Tumor microenvironment in ovarian cancer: Function and therapeutic strategy. Front Cell Dev Biol 2020; 8: 758.
21. Kim S, Han Y, Kim SI, Kim HS, Kim SJ and Song YS. Tumor evolution and chemoresistance in ovarian cancer. NPJ Precis Oncol 2018; 2:20.
22. Zhang Y, Cao L, Nguyen D and Lu H. TP53 mutations in epithelial ovarian cancer. Transl Cancer Res 2016; 5: 650-63.
23. Alatise KL, Gardner S and Alexander-Bryant A. Mechanisms of drug resistance in ovarian cancer and associated gene targets. Cancers (Basel) 2022; 14: 6246.
24. Parzych KR and Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 2014; 20: 460-73.
25. Feng Y, He D, Yao Z and Klionsky DJ. The machinery of macroautophagy. Cell Res 2014; 24: 24-41.
26. Hansen M, Rubinsztein DC and Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 2018; 19: 579-93.
27. Li X, Zhou Y, Li Y, Yang L, Ma Y, Peng X, Yang S, Liu J and Li H. Autophagy: A novel mechanism of chemoresistance in cancers. Biomed Pharmacother 2019; 119: 109415.
28. Bao L, Jaramillo MC, Zhang Z, Zheng Y, Yao M, Zhang DD and Yi X. Induction of autophagy contributes to cisplatin resistance in human ovarian cancer cells. Mol Med Rep 2015; 11: 91-8.
29. Zhang SF, Wang XY, Fu ZQ, Peng QH, Zhang JY, Ye F, Fu YF, Zhou CY, Lu WG, Cheng XD and Xie X. TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer. Autophagy 2015; 11: 225-38.
30. Chen J, Wang Q, Yin FQ, Zhang W, Yan LH and Li L. MTRR silencing inhibits growth and cisplatin resistance of ovarian carcinoma via inducing apoptosis and reducing autophagy. Am J Transl Res 2015; 7: 1510-27.
31. Yin X, Zhang N and Di W. Regulation of LC3-dependent protective autophagy in ovarian cancer cells by protein phosphatase 2A. Int J Gynecol Cancer 2013; 23: 630-41.
32. Zhan L, Zhang Y, Wang W, Song E, Fan Y, Li J and Wei B. Autophagy as an emerging therapy target for ovarian carcinoma. Oncotarget 2016; 7: 83476-87.
33. Wen Y, Graybill WS, Previs RA, Hu W, Ivan C, Mangala LS, Zand B, Nick AM, Jennings NB, Dalton HJ, Sehgal V, Ram P, Lee JS, Vivas-Mejia PE, Coleman RL and Sood AK. Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer. Clin Cancer Res 2015; 21: 448-59.
34. Pang Y, Si M, Sun B, Niu L, Xu X, Lu T, Yuan H and Lou H. DHA2, a synthesized derivative of bisbibenzyl, exerts antitumor activity against ovarian cancer through inhibition of XIAP and Akt/mTOR pathway. Food Chem Toxicol 2014; 69: 163-74.
35. Jin Z, Zheng L, Xin X, Li Y, Hua T, Wu T and Wang H. Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro. Mol Med Rep 2014; 10: 3099-105.
36. Wen Y, Graybill WS, Previs RA, Hu W, Ivan C, Mangala LS, Zand B, Nick AM, Jennings NB, Dalton HJ, Sehgal V, Ram P, Lee JS, Vivas-Mejia PE, Coleman RL and Sood AK. Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer. Clin Cancer Res 2015; 21: 448-59.
37. Sui H, Shi C, Yan Z and Li H. Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy. Drug Des Devel Ther 2015; 9: 3183-90.
38. Khurana A, Roy D, Kalogera E, Mondal S, Wen X, He X, Dowdy S and Shridhar V. Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth. Oncotarget 2015; 6: 36354-69.
39. Škubník J, Svobodová Pavlíčková V, Ruml T and Rimpelová S. Autophagy in cancer resistance to paclitaxel: Development of combination strategies. Biomed Pharmacother 2023 May; 161: 114458.
40. Stasiulewicz A, Znajdek K, Grudzień M, Pawiński T and Sulkowska AJI. A guide to targeting the endocannabinoid system in drug design. Int J Mol Sci 2020; 21: 2778.
41. Walker OS, Holloway AC and Raha S. The role of the endocannabinoid system in female reproductive tissues. J Ovarian Res 2019; 12: 3.
42. Leo LM and Abood ME. CB1 Cannabinoid receptor signaling and biased signaling. Molecules 2021; 26: 5413.
43. Singh K, Nassar N, Bachari A, Schanknecht E, Telukutla S, Zomer R, Piva TJ and Mantri N. The Pathophysiology and the therapeutic potential of cannabinoids in prostate cancer. Cancers (Basel) 2021; 13: 4107.
44. Saroz Y, Kho DT, Glass M, Graham ES and Grimsey NL. Cannabinoid receptor 2 (CB2) signals via G-alpha-s and induces IL-6 and IL-10 cytokine secretion in human primary leukocytes. ACS Pharmacol Transl Sci 2019; 2: 414-28.
45. Svízenská I, Dubový P and Sulcová A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures--a short review. Pharmacol Biochem Behav 2008; 90: 501-11.
46. Scotchie JG, Savaris RF, Martin CE and Young SL. Endocannabinoid regulation in human endometrium across the menstrual cycle. Reprod Sci 2015; 22: 113-23.
47. El-Talatini MR, Taylor AH, Elson JC, Brown L, Davidson AC and Konje JC. Localisation and function of the endocannabinoid system in the human ovary. PLoS One 2009; 4: e4579.
48. Bagavandoss P and Grimshaw S. Temporal and spatial distribution of the cannabinoid receptors (CB1, CB2) and fatty acid amide hydroxylase in the rat ovary. Anat Rec (Hoboken) 2010; 293: 1425-32.
49. Gebeh AK, Willets JM, Marczylo EL, Taylor AH and Konje JC. Ectopic pregnancy is associated with high anandamide levels and aberrant expression of FAAH and CB1 in fallopian tubes. J Clin Endocrinol Metab 2012; 97: 2827-35.
50. El-Talatini MR, Taylor AH and Konje JC. The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle. Fertil Steril 2010; 93: 1989-96.
51. Blanton HL, McHann MC, De Selle H, Dancel CL, Redondo JL, Molehin D, German NA, Trasti S, Pruitt K, Castro-Piedras I and Guindon J. Chronic administration of cannabinoid receptor 2 agonist (JWH-133) increases ectopic ovarian tumor growth and endocannabinoids (anandamide and 2-arachidonoyl glycerol) levels in immunocompromised SCID female mice. Front Pharmacol 2022; 13: 823132.
52. Kabakchieva P, Gateva A, Hristova J, Georgiev T and Kamenov Z. Analysis of 2-arachidonoylglycerol levels in polycystic ovary syndrome in the context of hormonal and metabolic alterations and across the classical phenotypes. Cannabis Cannabinoid Res 2023; 8: 634-41.
53. Messalli EM, Grauso F, Luise R, Angelini A and Rossiello R. Cannabinoid receptor type 1 immunoreactivity and disease severity in human epithelial ovarian tumors. Am J Obstet Gynecol 2014; 211: 234.e1-6.
54. Luschnig P and Schicho R. Cannabinoids in gynecological diseases. Med Cannabis Cannabinoids. 2019; 2: 14-21.
55. Iozzo M, Sgrignani G, Comito G, Chiarugi P and Giannoni E. Endocannabinoid system and tumour microenvironment: New intertwined connections for anticancer approaches. Cells 2021; 10: 3396.
56. Velasco G, Sánchez C and Guzmán M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer 2012; 12: 436-44.
57. Tegeder I. Endocannabinoids as guardians of metastasis. Int J Mol Sci 2016; 17: 230.
58. Schwarz R, Ramer R and Hinz B. Targeting the endocannabinoid system as a potential anticancer approach. Drug Metab Rev 2018; 50: 26-53.
59. Guindon J and Hohmann AG. The endocannabinoid system and cancer: therapeutic implication. Br J Pharmacol 2011; 163: 1447-63.
60. Pisanti S, Picardi P, D'Alessandro A, Laezza C and Bifulco M. The endocannabinoid signaling system in cancer. Trends Pharmacol Sci 2013; 34: 273-82.
61. Ayakannu T, Taylor AH, Willets JM and Konje JC. The evolving role of the endocannabinoid system in gynaecological cancer. Hum Reprod Update 2015; 21: 517-35.
62. Ligresti A, De Petrocellis L and Di Marzo V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: Pleiotropic physiological and pathological roles through complex pharmacology. Physiol Rev 2016; 96: 1593-659.
63. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 2008; 7: 438-55.
64. Calvaruso G, Pellerito O, Notaro A and Giuliano M. Cannabinoid-associated cell death mechanisms in tumor models (review). Int J Oncol 2012; 41: 407-13.
65. Carracedo A, Gironella M, Lorente M, Garcia S, Guzmán M, Velasco G and Iovanna JL. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 2006; 66: 6748-55.
66. Vara D, Salazar M, Olea-Herrero N, Guzmán M, Velasco G and Díaz-Laviada I. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ 2011; 18: 1099-111.
67. Armstrong JL, Hill DS, McKee CS, Hernandez-Tiedra S, Lorente M, Lopez-Valero I, Eleni Anagnostou M, Babatunde F, Corazzari M, Redfern CPF, Velasco G and Lovat PE. Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death. J Invest Dermatol 2015; 135: 1629-37.
68. Salazar M, Carracedo A, Salanueva IJ, Hernández-Tiedra S, Lorente M, Egia A, Vázquez P, Blázquez C, Torres S, García S, Nowak J, Fimia GM, Piacentini M, Cecconi F, Pandolfi PP, González-Feria L, Iovanna JL, Guzmán M, Boya P and Velasco G. Cannabinoid action induced autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest 2009; 119: 1359-72.
69. Worster B, Hajjar ER and Handley N. Cannabis use in patients with cancer: A clinical review. JCO Oncol Pract 2022; 18: 743-49.
70. Legare CA, Raup-Konsavage WM and Vrana KE. Therapeutic potential of cannabis, cannabidiol, and cannabinoid-based pharmaceuticals. Pharmacology 2022; 107: 131-49.
71. Sharma C, Sadek B, Goyal SN, Sinha S, Kamal MA and Ojha S. Small molecules from nature targeting G-protein coupled cannabinoid receptors: potential leads for drug discovery and development. Evid Based Complement Alternat Med 2015; 2015: 238482.
72. Bikman BT and Summers SA. Ceramides as modulators of cellular and whole-body metabolism. J Clin Invest 2011; 121: 4222-30.
73. Fahy E, Subramaniam S, Brown HA, Glass CK, Merrill AH Jr, Murphy RC, Raetz CR, Russell DW, Seyama Y, Shaw W, Shimizu T, Spener F and van Meer G, VanNieuwenhze MS, White SH, Witztum JL, Dennis EA. A comprehensive classification system for lipids. J Lipid Res 2005; 46: 839-61.
74. Pani T, Rajput K, Kar A, Sharma H, Basak R, Medatwal N, Saha S, Dev G, Kumar S, Gupta S, Mukhopadhyay A, Malakar D, Maiti TK, Arimbasseri AG, Deo SVS, Sharma RD, Bajaj A and Dasgupta U. Alternative splicing of ceramide synthase 2 alters levels of specific ceramides and modulates cancer cell proliferation and migration in Luminal B breast cancer subtype. Cell Death Dis 2021; 12: 171.
75. Pal P, Atilla-Gokcumen GE and Frasor J. Emerging roles of ceramides in breast cancer biology and therapy. Int J Mol Sci 2022; 23: 11178.
76. Zou J and Jian L. Inhibition of ceramide kinase ss effective against cisplatin-resistant ovarian cancer cells by regulating ceramide and C1P Levels. Gynecol Obstet Invest 2023; 88: 61-70.
77. Kitatani K, Usui T, Sriraman SK, Toyoshima M, Ishibashi M, Shigeta S, Nagase S, Sakamoto M, Ogiso H, Okazaki T, Hannun YA, Torchilin VP and Yaegashi N. Ceramide limits phosphatidylinositol-3-kinase C2β-controlled cell motility in ovarian cancer: potential of ceramide as a metastasis-suppressor lipid. Oncogene 2016; 35: 2801-12.
78. Zhang X, Sakamoto W, Canals D, Ishibashi M, Matsuda M, Nishida K, Toyoshima M, Shigeta S, Taniguchi M, Senkal CE, Okazaki T, Yaegashi N, Hannun YA, Nabe T and Kitatani K. Ceramide synthase 2-C24:1 -ceramide axis limits the metastatic potential of ovarian cancer cells. FASEB J 2021; 35: e21287.
79. Guzmán M, Galve-Roperh I and Sánchez C. Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol Sci 2001; 22: 19-22.
80. Gustafsson K, Sander B, Bielawski J, Hannun YA and Flygare J. Potentiation of cannabinoid-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism. Mol Cancer Res 2009; 7: 1086-98.
81. Herrera B, Carracedo A, Diez-Zaera M, Gómez del Pulgar T, Guzmán M and Velasco G. The CB2 cannabinoid receptor signals apoptosis via ceramide-dependent activation of the mitochondrial intrinsic pathway. Exp Cell Res 2006; 312: 2121-31.
82. Peralta ER and Edinger AL. Ceramide-induced starvation triggers homeostatic autophagy. Autophagy 2009; 5: 407-9.
83. Pattingre S, Bauvy C, Levade T, Levine B and Codogno P. Ceramide-induced autophagy: to junk or to protect cells? Autophagy 2009; 5: 558-60.
84. Pattingre S, Bauvy C, Carpentier S, Levade T, Levine B and Codogno P. Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. J Biol Chem 2009; 284: 2719-28.
85. Sun T, Li D, Wang L, Xia L, Ma J, Guan Z, Feng G and Zhu X. c-Jun NH2-terminal kinase activation is essential for up-regulation of LC3 during ceramide-induced autophagy in human nasopharyngeal carcinoma cells. J Transl Med 2011; 9: 161.
86. Park MA, Zhang G, Norris J, Hylemon PB, Fisher PB, Grant S and Dent P. Regulation of autophagy by ceramide-CD95-PERK signaling. Autophagy 2008; 4: 929-31.
87. Park MA, Zhang G, Martin AP, Hamed H, Mitchell C, Hylemon PB, Graf M, Rahmani M, Ryan K, Liu X, Spiegel S, Norris J, Fisher PB, Grant S and Dent P. Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol Ther 2008; 7: 1648-62.
88. Fazi B, Bursch W, Fimia GM, Nardacci R, Piacentini M, Di Sano F and Piredda L. Fenretinide induces autophagic cell death in caspase-defective breast cancer cells. Autophagy 2008; 4: 435-41.
89. Liu XW, Su Y, Zhu H, Cao J, Ding WJ, Zhao YC, He QJ and Yang B. HIF-1α-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia. Pharmacol Res 2010; 62: 416-25.
90. Messner MC and Cabot MC. Cytotoxic responses to N-(4-hydroxyphenyl)retinamide in human pancreatic cancer cells. Cancer Chemother Pharmacol 2011; 68: 477-87.
91. Morad SA and Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 2013; 13: 51-65.
92. Wang M and Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 2016; 529: 326-35.
93. Chen X and Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer 2021; 21: 71-88.
94. Cao S, Tang J, Huang Y, Li G, Li Z, Cai W, Yuan Y, Liu J, Huang X and Zhang H. The road of solid tumor survival: From drug-induced endoplasmic reticulum stress to drug resistance. Front Mol Biosci 2021; 8: 620514.
95. Lhomond S, Avril T, Dejeans N, Voutetakis K, Doultsinos D, McMahon M, Pineau R, Obacz J, Papadodima O, Jouan F, Bourien H, Logotheti M, Jégou G, Pallares-Lupon N, Schmit K, Le Reste PJ, Etcheverry A, Mosser J, Barroso K, Vauléon E, Maurel M, Samali A, Patterson JB, Pluquet O, Hetz C, Quillien V, Chatziioannou A and Chevet E. Dual IRE1 RNase functions dictate glioblastoma development. EMBO Mol Med 2018; 10: e7929.
96. Lam M, Marsters SA, Ashkenazi A and Walter P. Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress. Elife 2020; 9: e52291.
97. Song M, Sandoval TA, Chae CS, Chopra S, Tan C, Rutkowski MR, Raundhal M, Chaurio RA, Payne KK, Konrad C, Bettigole SE, Shin HR, Crowley MJP, Cerliani JP, Kossenkov AV, Motorykin I, Zhang S, Manfredi G, Zamarin D, Holcomb K, Rodriguez PC, Rabinovich GA, Conejo-Garcia JR, Glimcher LH and Cubillos-Ruiz JR. IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 2018; 562: 423-28.
98. Xu D, Liu Z, Liang MX, Fei YJ, Zhang W, Wu Y and Tang JH. Endoplasmic reticulum stress targeted therapy for breast cancer. Cell Commun Signal 2022; 20: 174.
99. Samanta S, Tamura S, Dubeau L, Mhawech-Fauceglia P, Miyagi Y, Kato H, Lieberman R, Buckanovich RJ, Lin YG and Neamati N. Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma. Sci Rep 2020; 10: 2160.
100. Xu Y, Wang C, Su J, Xie Q, Ma L, Zeng L, Yu Y, Liu S, Li S, Li Z and Sun L. Tolerance to endoplasmic reticulum stress mediates cisplatin resistance in human ovarian cancer cells by maintaining endoplasmic reticulum and mitochondrial homeostasis. Oncol Rep 2015; 34: 3051-60.
101. Drake MT, Shenoy SK and Lefkowitz RJ. Trafficking of G protein-coupled receptors. Circ Res 2006; 99: 570-82.
102. Esteban PF, Garcia-Ovejero D, Paniagua-Torija B, Moreno-Luna R, Arredondo LF, Zimmer A, Arevalo-Martin A and Molina-Holgado E. Revisiting CB1 cannabinoid receptor detection and the exploration of its interacting partners. J Neurosci Methods 2020; 337: 108680.
103. Marchalant Y, Brownjohn PW, Bonnet A, Kleffmann T and Ashton JC. Validating antibodies to the cannabinoid CB2 receptor: antibody sensitivity is not evidence of antibody specificity. J Histochem Cytochem 2014; 62: 395-404.
104. Jordà MA, Verbakel SE, Valk PJ, Vankan-Berkhoudt YV, Maccarrone M, Finazzi-Agrò A, Löwenberg B and Delwel R. Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2-arachidonoylglycerol. Blood 2002; 99: 2786-93.
105. Turu G, Soltész-Katona E, Tóth AD, Juhász C, Cserző M, Misák Á, Balla A, Caron MG and Hunyady L. Biased coupling to β-Arrestin of two common variants of the CB2 cannabinoid receptor. Front Endocrinol (Lausanne) 2021; 12: 714561.
106. Gyorffy B, Lánczky A and Szállási Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data of 1287 patients. Endocr Relat Cancer 2012; 19: 197-208.
107. Guida M, Ligresti A, De Filippis D, D'Amico A, Petrosino S, Cipriano M, Bifulco G, Simonetti S, Orlando P, Insabato L, Nappi C, Di Spiezio Sardo A, Di Marzo V and Iuvone T. The levels of the endocannabinoid receptor CB2 and its ligand 2-arachidonoylglycerol are elevated in endometrial carcinoma. Endocrinology 2010; 151: 921-8.
108. Nunn A, Guy G and Bell JD. Endocannabinoids in neuroendopsychology: multiphasic control of mitochondrial function. Philos Trans R Soc Lond B Biol Sci 2012; 367: 3342-52.
109. Yorimitsu T, Nair U, Yang Z and Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem 2006; 281: 30299-304.
110. Rashid HO, Yadav RK, Kim HR and Chae HJ. ER stress: Autophagy induction, inhibition and selection. Autophagy 2015; 11: 1956-77.
111. Chang H and Zou Z. Targeting autophagy to overcome drug resistance: further developments. J Hematol Oncol 2020; 13: 159.
112. Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem 2010; 17: 1468-86.
113. Khunluck T, Lertsuwan K, Chutoe C, Sooksawanwit S, Inson I, Teerapornpuntakit J, Tohtong R and Charoenphandhu N. Activation of cannabinoid receptors in breast cancer cells improves osteoblast viability in cancer-bone interaction model while reducing breast cancer cell survival and migration. Sci Rep 2022; 12: 7398.
114. Cianchi F, Papucci L, Schiavone N, Lulli M, Magnelli L, Vinci MC, Messerini L, Manera C, Ronconi E, Romagnani P, Donnini M, Perigli G, Trallori G, Tanganelli E, Capaccioli S and Masini E. Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin Cancer Res 2008; 14: 7691-700.
115. Deng YM, Zhao C, Wu L, Qu Z and Wang XY. Cannabinoid receptor-1 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR. Cell Death Discov 2022; 8: 273.
116. Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S, Salazar M, García-Taboada E, Barcia J, Guzmán M and Velasco G. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol Cancer Ther 2011; 10: 90-103.
117. Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, Jorcano JL and Guzmán M. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 2003; 111: 43-50.
118. McKallip RJ, Lombard C, Fisher M, Martin BR, Ryu S, Grant S, Nagarkatti PS and Nagarkatti M. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 2002; 100: 627-34.
119. Bettiga A, Aureli M, Colciago G, Murdica V, Moschini M, Lucianò R, Canals D, Hannun Y, Hedlund P, Lavorgna G, Colombo R, Bassi R, Samarani M, Montorsi F, Salonia A and Benigni F. Bladder cancer cell growth and motility implicate cannabinoid 2 receptor-mediated modifications of sphingolipids metabolism. Sci Rep 2017; 7: 42157.
120. Song S, Tan J, Miao Y and Zhang Q. Crosstalk of ER stress-mediated autophagy and ER-phagy: Involvement of UPR and the core autophagy machinery. J Cell Physiol 2018; 233: 3867-74.
121. Lin Y, Jiang M, Chen W, Zhao T and Wei Y. Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response. Biomed Pharmacother 2019; 118: 109249.
122. Wang J, Xu Y, Zou Y, Zhu L, Dong B, Huang J, Chen Y, Xue W, Huang Y, Kong W and Zhang J. Overexpression of cannabinoid receptor 1 promotes renal cell carcinoma progression. Tumour Biol 2016; 37: 16237-47.
123. Li LT, Zhao FF, Jia ZM, Qi LQ, Zhang XZ, Zhang L, Li YY, Yang JJ, Wang SJ, Lin H, Liu CH, An DD, Huang YQ and Gao XL. Cannabinoid receptors promote chronic intermittent hypoxia-induced breast cancer metastasis via IGF-1R/AKT/GSK-3β. Mol Ther Oncolytics 2021; 23: 220-30.
124. Chung SC, Hammarsten P, Josefsson A, Stattin P, Granfors T, Egevad L, Mancini G, Lutz B, Bergh A and Fowler CJ. A high cannabinoid CB(1) receptor immunoreactivity is associated with disease severity and outcome in prostate cancer. Eur J Cancer 2009; 45: 174-82.
125. Qamri Z, Preet A, Nasser MW, Bass CE, Leone G, Barsky SH and Ganju RK. Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Mol Cancer Ther 2009; 8: 3117-29.
126. Cui N, Wang L, Wang W, Zhang J, Xu Y, Jiang L and Hao G. The correlation of anandamide with gonadotrophin and sex steroid hormones during the menstrual cycle. Iran J Basic Med Sci 2017; 20: 1268-74.
127. Fuchs Weizman N, Wyse BA, Szaraz P, Defer M, Jahangiri S and Librach CL. Cannabis alters epigenetic integrity and endocannabinoid signalling in the human follicular niche. Hum Reprod 2021; 36: 1922-31.
128. Christie S, O'Rielly R, Li H, Wittert GA and Page AJ. Biphasic effects of methanandamide on murine gastric vagal afferent mechanosensitivity. J Physiol 2020; 598: 139-50.
129. Rodríguez-Manzo G and Canseco-Alba A. Biphasic effects of anandamide on behavioural responses: emphasis on copulatory behaviour. Behav Pharmacol 2015; 26: 607-15.
130. Lin Y, Shia KS, Hsiao WC, Hsieh WP, Yeh TK, Tseng SL, Hsu CY, Chao YS and Hung MS. Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities. Pharmacol Res 2010; 62: 337-43.
131. Soliman E, Henderson KL, Danell AS and Van Dross R. Arachidonoyl-ethanolamide activates endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase-2 and novel J-series prostamides. Mol Carcinog 2016; 55: 117-30.
132. Almada M, Costa L, Fonseca B, Alves P, Braga J, Gonçalves D, Teixeira N and Correia-da-Silva G. The endocannabinoid 2-arachidonoylglycerol promotes endoplasmic reticulum stress in placental cells. Reproduction 2020; 160: 171-80.
133. Donadelli M, Dando I, Zaniboni T, Costanzo C, Dalla Pozza E, Scupoli MT, Scarpa A, Zappavigna S, Marra M, Abbruzzese A, Bifulco M, Caraglia M and Palmieri M. Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism. Cell Death Dis 2011; 2: e152.
134. Go YY, Kim SR, Kim DY, Chae SW and Song JJ. Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep 2020; 10: 20622.
135. Wang J and Wu GS. Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem 2014; 289: 17163-73.
136. Ren JH, He WS, Nong L, Zhu QY, Hu K, Zhang RG, Huang LL, Zhu F and Wu G. Acquired cisplatin resistance in human lung adenocarcinoma cells is associated with enhanced autophagy. Cancer Biother Radiopharm 2010; 25: 75-80.
137. Sumkhemthong S, Prompetchara E, Chanvorachote P and Chaotham C. Cisplatin-induced hydroxyl radicals mediate pro-survival autophagy in human lung cancer H460 cells. Biol Res 2021; 54: 22.
138. DeMorrow S, Francis H, Gaudio E, Venter J, Franchitto A, Kopriva S, Onori P, Mancinelli R, Frampton G, Coufal M, Mitchell B, Vaculin B and Alpini G. The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway. Am J Physiol Gastrointest Liver Physiol 2008; 295: G1150-8.
139. Maradonna F, Fontana CM, Sella F, Giommi C, Facchinello N, Rampazzo C, Caichiolo M, Hoseinifar SH, Dalla Valle L, Van Doan H and Carnevali O. A zebrafish HCT116 xenograft model to predict anandamide outcomes on colorectal cancer. Cell Death Dis 2022; 13: 1069.
140. Portella G, Laezza C, Laccetti P, De Petrocellis L, Di Marzo V and Bifulco M. Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J 2003; 17: 1771-3.
141. Khan MI, Sobocińska AA, Brodaczewska KK, Zielniok K, Gajewska M, Kieda C, Czarnecka AM and Szczylik C. Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma. BMC Cancer 2018; 18: 583.