Thuốc chống loạn thần đã được tái sử dụng chlorpromazine ức chế ung thư đại trực tràng và di căn phổi bằng cách gây ngưng đọng chu kỳ tế bào G2/M, apoptosis và tự thực bào

Cancer Chemotherapy and Pharmacology - Tập 89 - Trang 331-346 - 2022
Fuyan Xu1,2,3, Huizhi Xi2, Mengya Liao4, Yiqian Zhang5, Hongbo Ma5, Mengling Wu2, Qiang Xue1, Hongbao Sun6, Yiwen Zhang2, Yong Xia1,2,3
1Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China
2State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
3Key Laboratory of Rehabilitation Medicine in Sichuan Province/Rehabilitation Medicine Research Institute, Chengdu, China
4Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
5West China School of Pharmacy, Sichuan University, Chengdu, China
6Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, China

Tóm tắt

Mặc dù đã có nhiều nỗ lực trong việc phát triển các chiến lược điều trị hiệu quả, ung thư đại trực tràng (CRC) vẫn là một trong những khối u phổ biến và gây tử vong nhất. Tái sử dụng các thuốc đã được phê duyệt là một chiến lược hấp dẫn để phát triển các tác nhân chống ung thư. Một số thuốc chống loạn thần, bao gồm chlorpromazine (CPZ), có hoạt tính chống ung thư. Tuy nhiên, tác động dược lý của CPZ đối với CRC chưa được xác định rõ ràng. Các thử nghiệm MTT, phân tích dòng chảy tế bào, phân tích western blot, mô hình khối u dưới da ở chuột và mô hình di căn phổi qua tiêm tĩnh mạch đuôi đã được sử dụng để điều tra các tác dụng chống ung thư của CPZ đối với CRC và cơ chế tiềm ẩn. Chúng tôi phát hiện rằng CPZ ức chế hiệu quả CRC bằng cách gây ngưng đọng chu kỳ tế bào G2/M và apoptosis. Ngưng đọng chu kỳ tế bào có liên quan đến việc giảm hoạt động của phức hợp cdc2/cyclin B1, bao gồm việc ức chế biểu hiện của cyclin B1, cdc2 và cdc25c, cùng với việc nâng cao mức độ biểu hiện của cdc2 phosphoryl hóa (Tyr15). Hơn nữa, CPZ ức chế tiềm năng màng ti thể và nâng cao mức độ các loài oxy phản ứng trong tế bào ung thư, cho thấy nó kích thích apoptosis nội tại phụ thuộc vào ti thể. CPZ đã chặn dòng chảy tự thực bào và kích thích tự thực bào độc tế bào trong các tế bào CRC. Ngoài ra, CPZ ức chế sự phát triển của khối u trong hai mô hình chuột dưới da mà không gây ra tác dụng phụ rõ rệt. Phân tích sự phong phú của các tế bào miễn dịch trong môi trường khối u cho thấy CPZ không ảnh hưởng đến tỷ lệ của chúng. Hơn nữa, nó ức chế đáng kể di căn phổi của các tế bào CT26 và kéo dài tuổi thọ của chuột. Những phát hiện này chỉ ra rằng việc tái sử dụng CPZ là một chiến lược điều trị mới cho bệnh nhân CRC.

Từ khóa

#ung thư đại trực tràng #chlorpromazine #apoptosis #chu kỳ tế bào #tự thực bào #di căn phổi

Tài liệu tham khảo

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660 Baum M, Fallowfield L, Farewell V, Macbeth F, Treasure T (2020) NICE guidelines: management of colorectal cancer metastases. Br J Surg 107(9):e357. https://doi.org/10.1002/bjs.11789 Ayati A, Moghimi S, Salarinejad S, Safavi M, Pouramiri B, Foroumadi A (2020) A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy. Bioorg Chem 99:103811. https://doi.org/10.1016/j.bioorg.2020.103811 Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18(1):41–58. https://doi.org/10.1038/nrd.2018.168 Gupta SC, Sung B, Prasad S, Webb LJ, Aggarwal BB (2013) Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci 34(9):508–517 Dilly SJ, Clark AJ, Marsh A, Mitchell DA, Cain R, Fishwick CWG, Taylor PC (2017) A chemical genomics approach to drug reprofiling in oncology: antipsychotic drug risperidone as a potential adenocarcinoma treatment. Cancer Lett 393:16–21 Chou FH, Tsai KY, Su CY, Lee CC (2011) The incidence and relative risk factors for developing cancer among patients with schizophrenia: a nine-year follow-up study. Schizophr Res 129(2–3):97–103 Dalton S, Johansen C, Ah NM, Sorensen H, Mclaughlin J, Mortensen P, Friis S (2006) Cancer risk among users of neuroleptic medication: a population-based cohort study. Brit J Cancer 95(7):934–939 Xu F, Xia Y, Feng Z, Lin W, Xue Q, Jiang J, Yu X, Peng C, Luo M, Yang Y, Wei Y, Yu L (2019) Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases. Am J Cancer Res 9(3):459–478 Xia Y, Xu F, Xiong M, Yang H, Lin W, Xie Y, Xi H, Xue Q, Ye T, Yu L (2021) Repurposing of antipsychotic trifluoperazine for treating brain metastasis, lung metastasis and bone metastasis of melanoma by disrupting autophagy flux. Pharmacol Res 163:105295. https://doi.org/10.1016/j.phrs.2020.105295 Oliva CR, Zhang W, Langford C, Suto MJ, Griguer CE (2017) Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit. Oncotarget 8(23):37568–37583 Shin SY, Lee KS, Choi YK, Lim HJ, Lee HG, Lim Y, Lee YH (2013) The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells. Carcinogenesis 34(9):2080–2089 Yang CE, Lee WY, Cheng HW, Chung CH, Mi FL, Lin CW (2019) The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells. Chem Biol Interact 302:28–35. https://doi.org/10.1016/j.cbi.2019.01.033 Lee WY, Lee WT, Cheng CH, Chen KC, Chou CM, Chung CH, Sun MS, Cheng HW, Ho MN, Lin CW (2015) Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1. Oncotarget 6(29):27580–27595. https://doi.org/10.18632/oncotarget.4768 Xia Y, Jia C, Xue Q, Jiang J, Xie Y, Wang R, Ran Z, Xu F, Zhang Y, Ye T (2019) Antipsychotic drug trifluoperazine suppresses colorectal cancer by inducing G0/G1 arrest and apoptosis. Front Pharmacol 10(1029):1–14. https://doi.org/10.3389/fphar.2019.01029 Sun Q, Yu X, Peng C, Liu N, Chen W, Xu H, Wei H, Fang K, Dong Z, Fu C, Xu Y, Lu W (2020) Activation of SREBP-1c alters lipogenesis and promotes tumor growth and metastasis in gastric cancer. Biomed Pharmacother 128:110274. https://doi.org/10.1016/j.biopha.2020.110274 Lu WJ, Peng W, Sun QQ, Li YH, Chen B, Yu LT, Xu YZ, Wang SY, Zhao YL (2018) #2714, a novel active inhibitor with potent G2/M phase arrest and antitumor efficacy in preclinical models. Cell death discovery 4:24. https://doi.org/10.1038/s41420-018-0032-y Liu N, Sun Q, Xu H, Yu X, Chen W, Wei H, Jiang J, Xu Y, Lu W (2020) Hyperuricemia induces lipid disturbances mediated by LPCAT3 upregulation in the liver. FASEB J: Off Publ Fed Am Soc Exp Biol 34(10):13474–13493. https://doi.org/10.1096/fj.202000950R Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP et al (2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)(1). Autophagy 17(1):1–382. https://doi.org/10.1080/15548627.2020.1797280 Yang L, Qiu Q, Tang M, Wang F, Yi Y, Yi D, Yang Z, Zhu Z, Zheng S, Yang J, Pei H, Zheng L, Chen Y, Gou L, Luo L, Deng X, Ye H, Hu Y, Niu T, Chen L (2019) Purinostat mesylate is a uniquely potent and selective inhibitor of HDACs for the treatment of BCR-ABL-induced B-cell acute lymphoblastic leukemia. Clin Cancer Res 25(24):7527–7539. https://doi.org/10.1158/1078-0432.ccr-19-0516 Wilhelm SM, Carter C, Tang LY, Wilkie D, McNabola A, Rong H, Chen C, Zhang XM, Vincent P, McHugh M, Cao YC, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64(19):7099–7109. https://doi.org/10.1158/0008-5472.can-04-1443 Bonelli M, La Monica S, Fumarola C, Alfieri R (2019) Multiple effects of CDK4/6 inhibition in cancer: from cell cycle arrest to immunomodulation. Biochem Pharmacol 170:113676. https://doi.org/10.1016/j.bcp.2019.113676 Chi V, Dang (2012) MYC on the path to cancer. Cell 149(1):22–35 Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G (2019) The molecular machinery of regulated cell death. Cell Res 29:347–364 Rodic S, Vincent MD (2018) Reactive oxygen species (ROS) are a key determinant of cancer’s metabolic phenotype. Int J Cancer 142(3):440–448. https://doi.org/10.1002/ijc.31069 Jhou AJ, Chang HC, Hung CC, Lin HC, Lee YC, Liu WT, Han KF, Lai YW, Lin MY, Lee CH (2021) Chlorpromazine, an antipsychotic agent, induces G2/M phase arrest and apoptosis via regulation of the PI3K/AKT/mTOR-mediated autophagy pathways in human oral cancer. Biochem Pharmacol 184:114403. https://doi.org/10.1016/j.bcp.2020.114403 Jiang J, Zhang L, Chen H, Lei Y, Zhang T, Wang Y, Jin P, Lan J, Zhou L, Huang Z, Li B, Liu Y, Gao W, Xie K, Zhou L, Nice EC, Peng Y, Cao Y, Wei Y, Wang K, Huang C (2020) Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma. Autophagy 16(1):106–122. https://doi.org/10.1080/15548627.2019.1598752 Chabanon RM, Muirhead G, Krastev DB, Adam J, Morel D, Garrido M, Lamb A, Henon C, Dorvault N, Rouanne M, Marlow R, Bajrami I, Cardenosa ML, Konde A, Besse B, Ashworth A, Pettitt SJ, Haider S, Marabelle A, Tutt ANJ, Soria J-C, Lord CJ, Postel-Vinay S (2019) PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer. J Clin Invest 129(3):1211–1228. https://doi.org/10.1172/jci123319 Michiel K, Paul G, Brok IC, Inna A, Hoogerbrugge PM, Adema GJ (2014) HDAC inhibitors and immunotherapy; a double edged sword? Oncotarget 5(16):6558–6572 Muric NN, Arsenijevic NN, Borovcanin MM (2020) Chlorpromazine as a potential antipsychotic choice in COVID-19 treatment. Front Psychiatry. https://doi.org/10.3389/fpsyt.2020.612347 Zucker S, Zarrabi HM, Schubach WH, Varma A, Derman R, Lysik RM, Habicht G, Seitz PM (1990) Chlorpromazine-induced immunopathy: progressive increase in serum IgM. Medicine 69(2):92–100 Bertini R, Garattini S, Delgado R, Ghezzi P (1993) Pharmacological activities of chlorpromazine involved in the inhibition of tumour necrosis factor production in vivo in mice. Immunology 79(2):217–219 Tarazona R, González-García A, Zamzami N, Marchetti P, Frechin N, Gonzalo JA, Ruiz-Gayo M, van Rooijen N, Martínez C, Kroemer G (1995) Chlorpromazine amplifies macrophage-dependent IL-10 production in vivo. J Immunol 154(2):861–870 Gadina M, Bertini R, Mengozzi M, Zandalasini M, Mantovani A, Ghezzi P (1991) Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. J Exp Med 173(6):1305–1310. https://doi.org/10.1084/jem.173.6.1305 Himmerich H, Schönherr J, Fulda S, Sheldrick AJ, Bauer K, Sack U (2011) Impact of antipsychotics on cytokine production in-vitro. J Psychiatr Res 45(10):1358–1365. https://doi.org/10.1016/j.jpsychires.2011.04.009 Labuzek K, Kowalski J, Gabryel B, Herman ZS (2005) Chlorpromazine and loxapine reduce interleukin-1β and interleukin-2 release by rat mixed glial and microglial cell cultures. Eur Neuropsychopharmacol 15(1):23–30. https://doi.org/10.1016/j.euroneuro.2004.04.002 Michl M, Thurmaier J, Schubert-Fritschle G, Wiedemann M, Laubender RP, Nüssler NC, Ruppert R, Kleeff J, Schepp W, Reuter C (2015) Brain metastasis in colorectal cancer patients: survival and analysis of prognostic factors. Clin Colorectal Cancer 14(4):281–290 Basso J, Miranda A, Sousa J, Pais A, Vitorino C (2018) Repurposing drugs for glioblastoma: from bench to bedside. Cancer Lett 428:173–183 Turanli B, Grøtli M, Boren J, Nielsen J, Uhlen M, Arga KY, Mardinoglu A (2018) Drug repositioning for effective prostate cancer treatment. Front Physiol 9:500 Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674 Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Proliferat 36(3):131–149 Kastan MB, Jiri B (2004) Cell-cycle checkpoints and cancer. Nature 432(7015):316 Badie C, Bourhis J, Sobczak-Thépot J, Haddada H, Chiron M, Janicot M, Janot F, Tursz T, Vassal G (2000) p53-dependent G2 arrest associated with a decrease in cyclins A2 and B1 levels in a human carcinoma cell line. Br J Cancer 82(3):642–650 Miller DM, Thomas SD, Ashraful I, David M, Kara S (2012) c-Myc and cancer metabolism. Clin Cancer Res 18(20):5546–5553 Fesik SW (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5(11):876–885 Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G (1997) Inhibition of Bax channel-forming activity by Bcl-2. Science 277(5324):370–372 Circu ML, Aw TY (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 48(6):749–762 Adams JL, Smothers J, Srinivasan R, Hoos A (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov 14(9):603–622 Wang M, Yin B, Wang HY, Wang RF (2014) Current advances in T-cell-based cancer immunotherapy. Immunotherapy 6(12):1265–1278. https://doi.org/10.2217/imt.14.86 Shimasaki N, Jain A, Campana D (2020) NK cells for cancer immunotherapy. Nat Rev Drug Discov 19(3):200–218. https://doi.org/10.1038/s41573-019-0052-1 Gardner A, Ruffell B (2016) Dendritic cells and cancer immunity. Trends Immunol 37(12):855–865. https://doi.org/10.1016/j.it.2016.09.006 Zhou J, Tang Z, Gao S, Li C, Feng Y, Zhou X (2020) Tumor-associated macrophages: recent insights and therapies. Front Oncol. https://doi.org/10.3389/fonc.2020.00188 Law AMK, Valdes-Mora F, Gallego-Ortega D (2020) Myeloid-derived suppressor cells as a therapeutic target for cancer. Cells. https://doi.org/10.3390/cells9030561 Park JH, Park HJ, Lee SE, Kim YS, Jang GY, Han HD, Jung ID, Shin KC, Bae YM, Kang TH, Park YM (2019) Repositioning of the antipsychotic drug TFP for sepsis treatment. J Mol Med (Berl) 97(5):647–658. https://doi.org/10.1007/s00109-019-01762-4 Gao Y, Bado I, Wang H, Zhang W, Rosen JM, Zhang XH-F (2019) Metastasis organotropism: redefining the congenial soil. Dev Cell 49(3):375–391 Mitry E, Guiu B, Cosconea S, Jooste V, Faivre J, Bouvier A-M (2010) Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut 59(10):1383–1388 Smith MA, Houghton P (2013) A proposal regarding reporting of in vitro testing results. Clin Cancer Res 19(11):2828–2833. https://doi.org/10.1158/1078-0432.ccr-13-0043 Yeung PK, Hubbard JW, Korchinski ED, Midha KK (1993) Pharmacokinetics of chlorpromazine and key metabolites. Eur J Clin Pharmacol 45(6):563–569. https://doi.org/10.1007/bf00315316 Bartelink IH, Jones EF, Shahidi-Latham SK, Lee PRE, Zheng Y, Vicini P, van’t Veer L, Wolf D, Iagaru A, Kroetz DL, Prideaux B, Cilliers C, Thurber GM, Wimana Z, Gebhart G (2019) Tumor drug penetration measurements could be the neglected piece of the personalized cancer treatment puzzle. Clin Pharmacol Ther 106(1):148–163. https://doi.org/10.1002/cpt.1211 Molenaar-Kuijsten L, van Meekeren M, Verheijen RB, Bovée JVMG, Fiocco M, Thijssen B, Rosing H, Huitema ADR, Miah AB, Gelderblom H, Haas RLM, Steeghs N (2021) Intra-tumoral pharmacokinetics of pazopanib in combination with radiotherapy in patients with non-metastatic soft-tissue sarcoma. Cancers 13(22):5780