Isoquercitrin inhibits the progression of pancreatic cancer in vivo and in vitro by regulating opioid receptors and the mitogen-activated protein kinase signalling pathway Retraction in /10.3892/or.2023.8505

Chen,Quan; Li,Ping; Li,Ping; Xu,Yong; Li,Yang; Tang,Bo

doi:10.3892/or.2014.3626

Isoquercitrin inhibits the progression of pancreatic cancer in vivo and in vitro by regulating opioid receptors and the mitogen-activated protein kinase signalling pathway

Retraction in: /10.3892/or.2023.8505

Authors:
- Quan Chen
- Ping Li
- Yong Xu
- Yang Li
- Bo Tang
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Affiliations: Department of Anesthesiology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China, Department of Oncology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China, Department of Hepatobiliary Surgery and Medical Oncology, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi 541001, P.R. China
Published online on: November 26, 2014 https://doi.org/10.3892/or.2014.3626
Pages: 840-848

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Abstract

Pancreatic cancer is a common malignant tumour that affects individuals worldwide. In recent years, the incidence and mortality rates of pancreatic cancer have continuously increased. Currently, the primary clinical treatment methods for pancreatic cancer include surgical resection, chemotherapy and radiotherapy. However, these treatment methods rarely produce satisfactory therapeutic outcomes. Extensive research has also proven that the effective components of several traditional Chinese medicines, particularly flavonoids extracted from plants, have significant antitumour effects. Isoquercitrin, which is one of the flavonoids found in Bidens pilosa extracts, has a significant antitumour effect. However, the antitumour effect of isoquercitrin and its mechanism of action remain unclear. The objective of the present study was to investigate the effect of isoquercitrin on the progression of pancreatic cancer and to further understand the biological characteristics of the participation of isoquercitrin in the progression of pancreatic cancer. In vitro, we found that a therapeutic dose of isoquercitrin significantly inhibited proliferation, promoted apoptosis and induced cell cycle arrest within the G1 phase in pancreatic cancer cells. Isoquercitrin activated caspase-3, -8 and -9 and reduced the mitochondrial membrane potential. In addition, isoquercitrin inhibited the expression level of the δ opioid receptor; however, isoquercitrin had no effect on the κ and µ opioid receptors. Furthermore, isoquercitrin inhibited extracellular signal-regulated kinase (ERK) phosphorylation and promoted c-Jun N-terminal kinase (JNK) phosphorylation. In vivo, we found that a therapeutic dose of isoquercitrin significantly inhibited xenograft growth in nude mice. In summary, the present study demonstrated that isoquercitrin inhibits human pancreatic cancer progression in vivo and in vitro and that its molecular mechanism may be closely related to opioid receptors and to the activation of the mitogen-activated protein kinase (MAPK) signalling pathway.

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1	Roy R and Maraveyas A: Chemoradiation in pancreatic adenocarcinoma: a literature review. Oncologist. 15:259–269. 2010. View Article : Google Scholar : PubMed/NCBI
2	Mian OY, Ram AN, Tuli R and Herman JM: Management options in locally advanced pancreatic cancer. Curr Oncol Rep. 16:3882014. View Article : Google Scholar : PubMed/NCBI
3	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar : PubMed/NCBI
4	Lockhart AC, Rothenberg ML and Berlin JD: Treatment for pancreatic cancer: current therapy and continued progress. Gastroenterology. 128:1642–1654. 2005. View Article : Google Scholar : PubMed/NCBI
5	Wray CJ, Ahmad SA, Matthews JB and Lowy AM: Surgery for pancreatic cancer: recent controversies and current practice. Gastroenterology. 128:1626–1641. 2005. View Article : Google Scholar : PubMed/NCBI
6	Gudjonsson B: Pancreatic cancer: survival errors and evidence. Eur J Gastroenterol Hepatol. 21:1379–1382. 2009. View Article : Google Scholar : PubMed/NCBI
7	Fulda S: Tumor resistance to apoptosis. Int J Cancer. 124:511–515. 2009. View Article : Google Scholar
8	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI
9	Tang J, Li N, Dai H and Wang K: Chemical constituents from seeds of Alpinia katsumadai, inhibition on NF-κB activation and anti-tumor effect. Zhongguo Zhong Yao Za Zhi. 35:1710–1714. 2010.(In Chinese). PubMed/NCBI
10	Ghosh A, Ghosh D, Sarkar S, Mandal AK, Thakur Choudhury S and Das N: Anticarcinogenic activity of nanoencapsulated quercetin in combating diethylnitrosamine-induced hepatocarcinoma in rats. Eur J Cancer Prev. 21:32–41. 2012. View Article : Google Scholar
11	Vogel S, Ohmayer S, Brunner G and Heilmann J: Natural and non-natural prenylated chalcones: synthesis, cytotoxicity and anti-oxidative activity. Bioorg Med Chem. 16:4286–4293. 2008. View Article : Google Scholar : PubMed/NCBI
12	Liu H, Dong A, Gao C, Tan C, Xie Z, Zu X, Qu L and Jiang Y: New synthetic flavone derivatives induce apoptosis of hepatocarcinoma cells. Bioorg Med Chem. 18:6322–6328. 2010. View Article : Google Scholar : PubMed/NCBI
13	Khan MS, Halagowder D and Devaraj SN: Methylated chrysin induces co-ordinated attenuation of the canonical Wnt and NF-kB signaling pathway and upregulates apoptotic gene expression in the early hepatocarcinogenesis rat model. Chem Biol Interact. 193:12–21. 2011. View Article : Google Scholar : PubMed/NCBI
14	Ullmannova V and Popescu NC: Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines. Cancer Detect Prev. 31:110–118. 2007. View Article : Google Scholar : PubMed/NCBI
15	Valentová K, Vrba J, Bancířová M, Ulrichová J and Křen V: Isoquercitrin: pharmacology, toxicology, and metabolism. Food Chem Toxicol. 68:267–282. 2014. View Article : Google Scholar : PubMed/NCBI
16	Liu Z, Zhang A, Guo Y and Dong C: Electrochemical sensor for ultrasensitive determination of isoquercitrin and baicalin based on DM-β-cyclodextrin functionalized graphene nanosheets. Biosens Bioelectron. 58:242–248. 2014. View Article : Google Scholar : PubMed/NCBI
17	Huang G, Tang B, Tang K, Dong X, Deng J, Liao L, Liao Z, Yang H and He S: Isoquercitrin inhibits the progression of liver cancer in vivo and in vitro via the MAPK signalling pathway. Oncol Rep. 31:2377–2384. 2014.PubMed/NCBI
18	Fujii Y, Kimura M, Ishii Y, Yamamoto R, Morita R, Hayashi SM, Suzuki K and Shibutani M: Effect of enzymatically modified isoquercitrin on preneoplastic liver cell lesions induced by thioacetamide promotion in a two-stage hepatocarcinogenesis model using rats. Toxicology. 305:30–40. 2013. View Article : Google Scholar : PubMed/NCBI
19	Shimada Y, Dewa Y, Ichimura R, Suzuki T, Mizukami S, Hayashi SM, Shibutani M and Mitsumori K: Antioxidant enzymatically modified isoquercitrin suppresses the development of liver preneoplastic lesions in rats induced by β-naphthoflavone. Toxicology. 268:213–218. 2010. View Article : Google Scholar : PubMed/NCBI
20	Amado NG, Cerqueira DM, Menezes FS, da Silva JF, Neto VM and Abreu JG: Isoquercitrin isolated from Hyptis fasciculata reduces glioblastoma cell proliferation and changes β-catenin cellular localization. Anticancer Drugs. 20:543–552. 2009. View Article : Google Scholar : PubMed/NCBI
21	Ono H, Basson MD and Ito H: PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling. PLoS One. 9:e960602014. View Article : Google Scholar : PubMed/NCBI
22	Takahashi R, Hirata Y, Sakitani K, Nakata W, Kinoshita H, Hayakawa Y, Nakagawa H, Sakamoto K, Hikiba Y, Ijichi H, Moses HL, Maeda S and Koike K: Therapeutic effect of c-Jun N-terminal kinase inhibition on pancreatic cancer. Cancer. 104:337–344. 2013.
23	Hornick JR, Vangveravong S, Spitzer D, Abate C, Berardi F, Goedegebuure P, Mach RH and Hawkins WG: Lysosomal membrane permeabilization is an early event in sigma-2 receptor ligand mediated cell death in pancreatic cancer. J Exp Clin Cancer Res. 31:412012. View Article : Google Scholar : PubMed/NCBI
24	Zagon IS and McLaughlin PJ: Targeting opioidergic pathways as a novel biological treatment for advanced pancreatic cancer. Expert Rev Gastroenterol Hepatol. 6:133–135. 2012. View Article : Google Scholar : PubMed/NCBI
25	Oliveira FQ, Andrade-Neto V, Krettli AU and Brandão MG: New evidences of antimalarial activity of Bidens pilosa roots extract correlated with polyacetylene and flavonoids. J Ethnopharmacol. 93:39–42. 2004. View Article : Google Scholar : PubMed/NCBI
26	Atta AH and Mouneir SM: Evaluation of some medicinal plant extracts for antidiarrhoeal activity. Phytother Res. 19:481–485. 2005. View Article : Google Scholar : PubMed/NCBI
27	Sukumaran P, Nair AG, Chinmayee DM, Mini I and Sukumaran ST: Phytochemical investigation of Bidens biternata (Lour.) Merr and Sheriff - a nutrient-rich leafy vegetable from Western Ghats of India. Appl Biochem Biotechnol. 167:1795–1801. 2012. View Article : Google Scholar : PubMed/NCBI
28	Yuan LP, Chen FH, Ling L, Bo H, Chen ZW, Li F, Zhong MM and Xia LJ: Protective effects of total flavonoids of Bidens bipinnata L. against carbon tetrachloride-induced liver fibrosis in rats. J Pharm Pharmacol. 60:1393–1402. 2008. View Article : Google Scholar : PubMed/NCBI
29	Yang QH, Yang J, Liu GZ, Wang L, Zhu TC, Gao HL and Kou XG: Study on in vitro anti-tumor activity of Bidens bipinnata L. extract. Afr J Tradit Complement Altern Med. 10:543–549. 2013.PubMed/NCBI
30	Kumari P, Misra K, Sisodia BS, Faridi U, Srivastava S, Luqman S, Darokar MP, Negi AS, Gupta MM, Singh SC and Kumar JK: A promising anticancer and antimalarial component from the leaves of Bidens pilosa. Planta Med. 75:59–61. 2009. View Article : Google Scholar
31	Ong PL, Weng BC, Lu FJ, Lin ML, Chang TT, Hung RP and Chen CH: The anticancer effect of protein-extract from Bidens alba in human colorectal carcinoma SW480 cells via the reactive oxidative species- and glutathione depletion-dependent apoptosis. Food Chem Toxicol. 46:1535–1547. 2008. View Article : Google Scholar : PubMed/NCBI
32	Wu J, Wan Z, Yi J, Wu Y, Peng W and Wu J: Investigation of the extracts from Bidens pilosa Linn. var radiata Sch Bip for antioxidant activities and cytotoxicity against human tumor cells. J Nat Med. 67:17–26. 2013. View Article : Google Scholar
33	Zhong MM, Chen FH, Yuan LP, Wang XH and Wu FR: Study on the property of adsorption and separation of the macroporous resins for total flavonoids of Bidens bipinnata L. Zhong Yao Cai. 30:338–341. 2007.(In Chinese). PubMed/NCBI
34	Lee S, Park HS, Notsu Y, Ban HS, Kim YP, Ishihara K, Hirasawa N, Jung SH, Lee YS, Lim SS, Park EH, Shin KH, Seyama T, Hong J and Ohuchi K: Effects of hyperin, isoquercitrin and quercetin on lipopolysaccharide-induced nitrite production in rat peritoneal macrophages. Phytother Res. 22:1552–1556. 2008. View Article : Google Scholar : PubMed/NCBI
35	Hirano T, Kawai M, Arimitsu J, Ogawa M, Kuwahara Y, Hagihara K, Shima Y, Narazaki M, Ogata A, Koyanagi M, Kai T, Shimizu R, Moriwaki M, Suzuki Y, Ogino S, Kawase I and Tanaka T: Preventative effect of a flavonoid, enzymatically modified isoquercitrin on ocular symptoms of Japanese cedar pollinosis. Allergol Int. 58:373–382. 2009. View Article : Google Scholar : PubMed/NCBI
36	Magalingam KB, Radhakrishnan A and Haleagrahara N: Protective effects of flavonol isoquercitrin, against 6-hydroxy dopamine (6-OHDA)-induced toxicity in PC12 cells. BMC Res Notes. 7:492014. View Article : Google Scholar : PubMed/NCBI
37	Li R, Yuan C, Dong C, Shuang S and Choi MM: In vivo antioxidative effect of isoquercitrin on cadmium-induced oxidative damage to mouse liver and kidney. Naunyn Schmiedebergs Arch Pharmacol. 383:437–445. 2011. View Article : Google Scholar : PubMed/NCBI
38	Gong WY, Wu JF, Liu BJ, Zhang HY, Cao YX, Sun J, Lv YB, Wu X and Dong JC: Flavonoid components in Scutellaria baicalensis inhibit nicotine-induced proliferation, metastasis and lung cancer-associated inflammation in vitro. Int J Oncol. 44:1561–1570. 2014.PubMed/NCBI
39	Bądziul D, Jakubowicz-Gil J, Paduch R, Głowniak K and Gawron A: Combined treatment with quercetin and imperatorin as a potent strategy for killing HeLa and Hep-2 cells. Mol Cell Biochem. 392:213–227. 2014. View Article : Google Scholar :
40	You OH and Kim SH, Kim B, Sohn EJ, Lee HJ, Shim BS, Yun M, Kwon BM and Kim SH: Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells. Bioorg Med Chem Lett. 23:2692–2695. 2013. View Article : Google Scholar : PubMed/NCBI
41	Mujumdar N, Banerjee S, Chen Z, Sangwan V, Chugh R, Dudeja V, Yamamoto M, Vickers SM and Saluja AK: Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol. 306:G1011–G1020. 2014. View Article : Google Scholar : PubMed/NCBI
42	Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH and Dyson NJ: CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16^INK4A-deficient pancreatic cancers. Cancer Res. 74:3947–3958. 2014. View Article : Google Scholar : PubMed/NCBI
43	Dewson G and Kluck RM: Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J Cell Sci. 122:2801–2808. 2009. View Article : Google Scholar : PubMed/NCBI
44	Fombonne J, Bissey PA, Guix C, Sadoul R, Thibert C and Mehlen P: Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9. Proc Natl Acad Sci USA. 109:10510–10515. 2012. View Article : Google Scholar : PubMed/NCBI
45	Kim H, Lee SW, Park JS, Min JH and Kim HK: Genomic analysis of [d-Ala², d-Leu⁵] enkephalin preconditioning in cortical neuron and glial cell injury after oxygen deprivation. Brain Res. 1447:91–105. 2012. View Article : Google Scholar : PubMed/NCBI
46	Galeotti N and Ghelardini C: Regionally selective activation and differential regulation of ERK, JNK and p38MAP kinase signalling pathway by protein kinase C in mood modulation. Int J Neuropsychopharmacol. 15:781–793. 2012. View Article : Google Scholar
47	Raman M, Chen W and Cobb MH: Differential regulation and properties of MAPKs. Oncogene. 26:3100–3112. 2007. View Article : Google Scholar : PubMed/NCBI
48	Robbs BK, Lucena PI and Viola JP: The transcription factor NFAT1 induces apoptosis through cooperation with Ras/Raf/MEK/ERK pathway and upregulation of TNF-α expression. Biochim Biophys Acta. 1833:2016–2028. 2013. View Article : Google Scholar : PubMed/NCBI
49	Dhanasekaran DN and Reddy EP: JNK signaling in apoptosis. Oncogene. 27:6245–6251. 2008. View Article : Google Scholar : PubMed/NCBI
50	Nateri AS, Spencer-Dene B and Behrens A: Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature. 437:281–285. 2005. View Article : Google Scholar : PubMed/NCBI
51	Alspach E, Flanagan KC, Luo X, Ruhland MK, Huang H, Pazolli E, Donlin MJ, Marsh T, Piwnica-Worms D, Monahan J, Novack DV, McAllister SS and Stewart SA: p38MAPK plays a crucial role in stromal-mediated tumorigenesis. Cancer Discov. 4:716–729. 2014. View Article : Google Scholar : PubMed/NCBI
52	Marengo B, De Ciucis CG, Ricciarelli R, Furfaro AL, Colla R, Canepa E, Traverso N, Marinari UM, Pronzato MA and Domenicotti C: p38MAPK inhibition: a new combined approach to reduce neuroblastoma resistance under etoposide treatment. Cell Death Dis. 4:e5892013. View Article : Google Scholar : PubMed/NCBI