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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

JDHY3 Inhibits Hypopharyngeal Carcinoma Cell Proliferation and Promotes Apoptosis by Inhibiting the PI3K/AKT Pathway

Author(s): Weili Dai, Zhen Ni, Ganlin Zhang, Jia Xu, Xiaoyan Qin, Jingpeng Cao and Liangfa Liu*

Volume 23, Issue 11, 2023

Published on: 13 March, 2023

Page: [1327 - 1335] Pages: 9

DOI: 10.2174/1871520623666230220152833

Price: $65

Abstract

Background: Jieduhuayu No.3 (JDHY3) is a modified Chinese herbal formula beneficial for treating hypopharyngeal carcinoma (HC), but its pharmacological mechanism is unknown.

Objective: This study aimed to explore the mechanism of the herbal formula JDHY3 in inhibiting cell proliferation and promoting apoptosis in HC in vitro and in vivo.

Methods: In this study, HC cells were treated with cisplatin and different concentrations of JDHY3. The apoptosis rate was detected by flow cytometry. Western blotting was used to detect the proteins related to cell proliferation and apoptosis. Afterward, the xenograft mouse model was established and treated with cisplatin and JDHY3. Mouse tumour volume was measured, and the tumour tissues were assessed by HE staining and immunohistochemistry.

Results: JDHY3 significantly inhibited the proliferation of FaDu and Detroit-562 cells. In addition, JDHY3 significantly increased the apoptosis rate of HC cells and downregulated p-PI3K and p-Akt. In addition, JDHY3 upregulated the expression of the apoptosis-promoting proteins Bax, P53, and cleaved caspase-3. In addition, the expression of the antiapoptotic protein Bcl-2 was downregulated. Coincubation with SC79 attenuated the decrease in cell proliferation induced by JDHY3, further confirming that the proapoptotic effect of JDHY3 is associated with the inhibition of PI3K/Akt pathway activation.

Conclusions: The results of in vivo experiments showed that JDHY3 could effectively inhibit the proliferation of HC cells, and HE staining showed that JDHY3 reduced the invasion of HC cells. Immunohistochemistry showed that the expression of P53 and cleaved caspase-3 was significantly increased in the tissues of the JDHY3-treated group.

Keywords: Hypopharyngeal carcinoma, proliferation, apoptosis, PI3K/Akt pathway, JDHY3, immunohistochemistry.

Graphical Abstract
[1]
Romanowska, K.; Sobecka, A.; Rawłuszko-Wieczorek, A.A.; Suchorska, W.M.; Golusiński, W. Head and neck squamous cell carcinoma: Epigenetic landscape. Diagnostics, 2020, 11(1), 34.
[http://dx.doi.org/10.3390/diagnostics11010034] [PMID: 33375464]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin., 2017, 67(1), 7-30.
[http://dx.doi.org/10.3322/caac.21387] [PMID: 28055103]
[3]
Zhu, G.; Peng, O.; Li, S.; Zhu, G.; Wang, S.; Liu, J.; Yin, D.; Peng, X.; Yang, T.; Tang, Q.; Yang, X. Three strategies for displaying the postcricoid space and pyriform sinus: A matched case-controlled study of 50 patients. Clin. Otolaryngol., 2019, 44(2), 187-190.
[http://dx.doi.org/10.1111/coa.13256] [PMID: 30411859]
[4]
Tan, H.Y.; Sanudin, S.H.; Lum, S.G.; Wong, E.H.C. An unusual first presentation of hypopharyngeal carcinoma as thyroid abscess: Case report of a diagnostic challenge. Int. J. Surg. Case Rep., 2021, 81105723.
[http://dx.doi.org/10.1016/j.ijscr.2021.105723] [PMID: 33713999]
[5]
Peng, X.; Liu, Y.; Zhu, S.; Peng, X.; Li, H.; Jiao, W.; Lin, P.; Zhang, Z.; Qiu, Y.; Jin, M.; Wang, R.; Kong, D. Co-targeting PI3K/Akt and MAPK/ERK pathways leads to an enhanced antitumor effect on human hypopharyngeal squamous cell carcinoma. J. Cancer Res. Clin. Oncol., 2019, 145(12), 2921-2936.
[http://dx.doi.org/10.1007/s00432-019-03047-2] [PMID: 31620898]
[6]
Visini, M.; Giger, R.; Shelan, M.; Elicin, O.; Anschuetz, L. Predicting factors for oncological and functional outcome in hypopharyngeal cancer. Laryngoscope, 2021, 131(5), E1543-E1549.
[http://dx.doi.org/10.1002/lary.29186] [PMID: 33098325]
[7]
Rong, L.; Li, Z.; Leng, X.; Li, H.; Ma, Y.; Chen, Y.; Song, F. Salidroside induces apoptosis and protective autophagy in human gastric cancer AGS cells through the PI3K/Akt/mTOR pathway. Biomed. Pharmacother., 2020, 122, 109726.
[http://dx.doi.org/10.1016/j.biopha.2019.109726] [PMID: 31918283]
[8]
Roudsari, N.M.; Lashgari, N.A.; Momtaz, S.; Abaft, S.; Jamali, F.; Safaiepour, P.; Narimisa, K.; Jackson, G.; Bishayee, A.; Rezaei, N.; Abdolghaffari, A.H.; Bishayee, A. Inhibitors of the PI3K/Akt/mTOR pathway in prostate cancer chemoprevention and intervention. Pharmaceutics, 2021, 13(8), 1195.
[http://dx.doi.org/10.3390/pharmaceutics13081195] [PMID: 34452154]
[9]
Iksen, L.; Pothongsrisit, S.; Pongrakhananon, V. Targeting the PI3K/AKT/mTOR signaling pathway in lung cancer: An update regarding potential drugs and natural products. Molecules, 2021, 26(13), 4100.
[http://dx.doi.org/10.3390/molecules26134100] [PMID: 34279440]
[10]
Zhou, R.; Liu, D.; Zhu, J.; Zhang, T. Common gene signatures and key pathways in hypopharyngeal and esophageal squamous cell carci-noma. Medicine, 2020, 99(42), e22434.
[http://dx.doi.org/10.1097/MD.0000000000022434] [PMID: 33080677]
[11]
Hsu, C.M.; Lin, P.M.; Tsai, Y.T.; Tsai, M.S.; Tseng, C.H.; Lin, S.F.; Yang, M.Y. NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin. Cell Death Discov., 2018, 4(1), 57.
[http://dx.doi.org/10.1038/s41420-018-0060-7] [PMID: 29760955]
[12]
Zhang, Y.; Cong, L.; He, J.; Wang, Y.; Zou, Y.; Yang, Z.; Hu, Y.; Zhang, S.; He, X. Photothermal treatment with EGFRmAb–AuNPs induc-es apoptosis in hypopharyngeal carcinoma cells via PI3K/AKT/mTOR and DNA damage response pathways. Acta Biochim. Biophys. Sin., 2018, 50(6), 567-578.
[http://dx.doi.org/10.1093/abbs/gmy046] [PMID: 29718150]
[13]
Guo, Q.; Lin, J.; Liu, R.; Gao, Y.; He, S.; Xu, X.; Hua, B.; Li, C.; Hou, W.; Zheng, H.; Bao, Y. Review on the applications and molecular mechanisms of xihuang pill in tumor treatment. Evid. Based Complement. Alternat. Med., 2015, 2015, 1-10.
[http://dx.doi.org/10.1155/2015/854307] [PMID: 26170886]
[14]
Yoon, B.K.; Lim, Z.Y.; Jeon, W.Y.; Cho, N.J.; Kim, J.H.; Jackman, J.A. Medicinal activities and nanomedicine delivery strategies for Brucea javanica oil and its molecular components. Molecules, 2020, 25(22), 5414.
[http://dx.doi.org/10.3390/molecules25225414] [PMID: 33228061]
[15]
Wang, M.; Mao, D.; Li, H. Chinese medicine jiedu huayu granules reduce liver injury in rats by regulating t-cell immunity. Evid. Based Complement. Alternat. Med., 2019, 2019, 1-8.
[http://dx.doi.org/10.1155/2019/1873541] [PMID: 31885638]
[16]
Qiu, H.; Mao, D.; Tang, N.; Long, F.; Zhang, R.; Wang, M.; Shi, Q.; Li, J.; Jiang, Q.; Chen, Y.; Wang, X. The underlying mechanisms of Jie-Du-Hua-Yu granule for protecting rat liver failure. Drug Des. Devel. Ther., 2019, 13, 589-600.
[http://dx.doi.org/10.2147/DDDT.S180969] [PMID: 30809090]
[17]
Raine, C.H.; Stell, P.M.; Dalby, J. Squamous cell carcinomas of the posterior wall of the hypopharynx. J. Laryngol. Otol., 1982, 96(11), 997-1004.
[http://dx.doi.org/10.1017/S0022215100093427] [PMID: 7130851]
[18]
Jol, J.K.A.D.; Quak, J.J.; de Bree, R.; Leemans, C.R. Larynx preservation surgery for advanced posterior pharyngeal wall carcinoma with free flap reconstruction: A critical appraisal. Oral Oncol., 2003, 39(6), 552-558.
[http://dx.doi.org/10.1016/S1368-8375(03)00037-X] [PMID: 12798397]
[19]
Kwon, D.I.; Miles, B.A. Hypopharyngeal carcinoma: Do you know your guidelines? Head Neck, 2019, 41(3), 569-576.
[http://dx.doi.org/10.1002/hed.24752] [PMID: 30570183]
[20]
Li, Y.; Yang, G.; Li, M.; Tong, X. Nursing observation on the clinical efficacy and toxicity of lobaplatin compared with cisplatin in the treatment of locally advanced hypopharyngeal carcinoma based on intelligent ct imaging. J. Healthc. Eng., 2021, 2021, 1-11.
[http://dx.doi.org/10.1155/2021/9982888] [PMID: 34306603]
[21]
Pavón, M.A.; Arroyo-Solera, I.; Céspedes, M.V.; Casanova, I.; León, X.; Mangues, R. uPA/uPAR and SERPINE1 in head and neck cancer: Role in tumor resistance, metastasis, prognosis and therapy. Oncotarget, 2016, 7(35), 57351-57366.
[http://dx.doi.org/10.18632/oncotarget.10344] [PMID: 27385000]
[22]
Pavón, M.A.; Arroyo-Solera, I.; Téllez-Gabriel, M.; León, X.; Virós, D.; López, M.; Gallardo, A.; Céspedes, M.V.; Casanova, I.; López-Pousa, A.; Mangues, M.A.; Quer, M.; Barnadas, A.; Mangues, R. Enhanced cell migration and apoptosis resistance may underlie the asso-ciation between high SERPINE1 expression and poor outcome in head and neck carcinoma patients. Oncotarget, 2015, 6(30), 29016-29033.
[http://dx.doi.org/10.18632/oncotarget.5032] [PMID: 26359694]
[23]
Bajou, K.; Peng, H.; Laug, W.E.; Maillard, C.; Noel, A.; Foidart, J.M.; Martial, J.A.; DeClerck, Y.A. Plasminogen activator inhibitor-1 pro-tects endothelial cells from fasl-mediated apoptosis. Cancer Cell, 2008, 14(4), 324-334.
[http://dx.doi.org/10.1016/j.ccr.2008.08.012] [PMID: 18835034]
[24]
Spangle, J.M.; Roberts, T.M.; Zhao, J.J. The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim. Biophys. Acta Rev. Cancer, 2017, 1868(1), 123-131.
[http://dx.doi.org/10.1016/j.bbcan.2017.03.002] [PMID: 28315368]
[25]
Mayer, I.A.; Arteaga, C.L. The PI3K/AKT pathway as a target for cancer treatment. Annu. Rev. Med., 2016, 67(1), 11-28.
[http://dx.doi.org/10.1146/annurev-med-062913-051343] [PMID: 26473415]
[26]
Dai, W.; Jin, X.; Jiang, B.; Chen, W.; Ji, Z.; Xu, X.; Tang, M.; Dai, K.; Han, L. Elevated o-glcnacylation promotes malignant phenotypes of hypopharyngeal squamous cell carcinoma by stabilizing nrf2 through regulation of the pi3k/akt pathway. Anticancer. Agents Med. Chem., 2020, 20(16), 1933-1942.
[http://dx.doi.org/10.2174/1871520620666200615132435] [PMID: 32538734]
[27]
Ju, S.H.; Tan, L.R.; Liu, P.W.; Tan, Y.L.; Zhang, Y.T.; Li, X.H.; Wang, M.J.; He, B.X. Scutellarin regulates osteoarthritis in vitro by inhibit-ing the PI3K/AKT/mTOR signaling pathway. Mol. Med. Rep., 2020, 23(1), 83.
[http://dx.doi.org/10.3892/mmr.2020.11722] [PMID: 33236146]
[28]
Cao, P.; Liu, B.; Du, F.; Li, D.; Wang, Y.; Yan, X.; Li, X.; Li, Y. Scutellarin suppresses proliferation and promotes apoptosis in A549 lung adenocarcinoma cells via AKT/mTOR/4EBP1 and STAT3 pathways. Thorac. Cancer, 2019, 10(3), 492-500.
[http://dx.doi.org/10.1111/1759-7714.12962] [PMID: 30666790]
[29]
Wang, L.; Yang, H.; Wang, C.; Shi, X.; Li, K. Rosmarinic acid inhibits proliferation and invasion of hepatocellular carcinoma cells SMMC 7721 via PI3K/AKT/mTOR signal pathway. Biomed. Pharmacother., 2019, 120109443.
[http://dx.doi.org/10.1016/j.biopha.2019.109443] [PMID: 31541884]
[30]
Yang, J.; Li, X.; Yang, H.; Long, C. Oleanolic acid improves the symptom of renal ischemia reperfusion injury via the pi3k/akt pathway. Urol. Int., 2021, 105(3-4), 215-220.
[http://dx.doi.org/10.1159/000506778] [PMID: 33291121]
[31]
Li, X.; Song, Y.; Zhang, P.; Zhu, H.; Chen, L.; Xiao, Y.; Xing, Y. Oleanolic acid inhibits cell survival and proliferation of prostate cancer cells in vitro and in vivo through the PI3K/Akt pathway. Tumour Biol., 2016, 37(6), 7599-7613.
[http://dx.doi.org/10.1007/s13277-015-4655-9] [PMID: 26687646]
[32]
Dai, W.L.; Liu, X.T.; Bao, Y.N.; Yan, B.; Jiang, N.; Yu, B.Y.; Liu, J.H. Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner. Exp. Mol. Med., 2018, 50(11), 1-12.
[http://dx.doi.org/10.1038/s12276-018-0175-1] [PMID: 30429454]

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