![Open Access](/resources/images/iconopenaccess.png)
Gemcitabine‑fucoxanthin combination in human pancreatic cancer cells
- Authors:
- Jun Lu
- Xiaowu Jenifer Wu
- Amira Hassouna
- Kelvin Sheng Wang
- Yan Li
- Tao Feng
- Yu Zhao
- Minfeng Jin
- Baohong Zhang
- Tianlei Ying
- Jinyao Li
- Lufeng Cheng
- Johnson Liu
- Yue Huang
-
Affiliations: College of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, P.R. China, Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1142, New Zealand, Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11956, Egypt, College of Life Sciences, Shanghai Normal University, Shanghai 200234, P.R. China, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P.R. China, Key Laboratory of Medical Molecular Virology of MOE/MOH, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China, Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830046, P.R. China, Department of Pharmacology, College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia, Shanghai Business School, Fengxian, Shanghai 201499, P.R. China - Published online on: June 1, 2023 https://doi.org/10.3892/br.2023.1629
- Article Number: 46
-
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
This article is mentioned in:
Abstract
![]() |
![]() |
American Cancer Society: Cancer Facts and Figures. American Cancer Society, Atlanta, pp1-56, 2017. | |
Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010.PubMed/NCBI View Article : Google Scholar | |
Neoptolemos JP, Urrutia R, Abbruzzese JL and Büchler MW: Pancreatic cancer. New York, NY, Springer, 2010. | |
Ministry of Health. Cancer programme. 2015. Retrieved March 19, 2015, from http://www.health.govt.nz/our-work/diseases-and-conditions/cancer-programme. | |
Bosetti C, Bertuccio P, Negri E, La Vecchia C, Zeegers MP and Boffetta P: Pancreatic cancer: Overview of descriptive epidemiology. Mol Carcinog. 51:3–13. 2012.PubMed/NCBI View Article : Google Scholar | |
Goodman KA and Hajj C: Role of radiation therapy in the management of pancreatic cancer. J Surg Oncol. 107:86–96. 2013.PubMed/NCBI View Article : Google Scholar | |
Morton JP, Timpson P, Karim SA, Ridgway RA, Athineos D, Doyle B, Jamieson NB, Oien KA, Lowy AM, Brunton VG, et al: Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci USA. 107:246–251. 2010.PubMed/NCBI View Article : Google Scholar | |
Mulcahy MF, Wahl AO and Small W Jr: The current status of combined radiotherapy and chemotherapy for locally advanced or resected pancreas cancer. J Natl Compr Canc Netw. 3:637–642. 2005.PubMed/NCBI View Article : Google Scholar | |
Peng J, Yuan JP, Wu CF and Wang JH: Fucoxanthin, a marine carotenoid present in brown seaweeds and diatoms: Metabolism and bioactivities relevant to human health. Mar Drugs. 9:1806–1828. 2011.PubMed/NCBI View Article : Google Scholar | |
Zhang H, Tang Y, Zhang Y, Zhang S, Qu J, Wang X, Kong R, Han C and Liu Z: Fucoxanthin: A promising medicinal and nutritional ingredient. Evid Based Complement Alternat Med. 2015(723515)2015.PubMed/NCBI View Article : Google Scholar | |
Beppu F, Niwano Y, Sato E, Kohno M, Tsukui T, Hosokawa M and Miyashita K: In vitro and in vivo evaluation of mutagenicity of fucoxanthin (FX) and its metabolite fucoxanthinol (FXOH). J Toxicol Sci. 34:693–698. 2009.PubMed/NCBI View Article : Google Scholar | |
Zorofchian Moghadamtousi S, Karimian H, Khanabdali R, Razavi M, Firoozinia M, Zandi K and Abdul Kadir H: Anticancer and antitumor potential of fucoidan and fucoxanthin, two main metabolites isolated from brown algae. ScientificWorldJournal. 2014(768323)2014.PubMed/NCBI View Article : Google Scholar | |
Haefner B: Drugs from the deep: Marine natural products as drug candidates. Drug Discov Today. 8:536–544. 2003.PubMed/NCBI View Article : Google Scholar | |
Aravindan S, Delma CR, Thirugnanasambandan SS, Herman TS and Aravindan N: Anti-pancreatic cancer deliverables from sea: First-hand evidence on the efficacy, molecular targets and mode of action for multifarious polyphenols from five different brown-algae. PLoS One. 8(e61977)2013.PubMed/NCBI View Article : Google Scholar | |
Gammone MA and D'Orazio N: Anti-obesity activity of the marine carotenoid fucoxanthin. Mar Drugs. 13:2196–2214. 2015.PubMed/NCBI View Article : Google Scholar | |
López-Rios L, Vega T, Chirino R, Jung JC, Davis B, Pérez-Machín R and Wiebe JC: Toxicological assessment of Xanthigen® nutraceutical extract combination: Mutagenicity, genotoxicity and oral toxicity. Toxicol Rep. 9:1021–1031. 2018.PubMed/NCBI View Article : Google Scholar | |
Delma CR, Thirugnanasambandan S, Srinivasan GP, Raviprakash N, Manna SK, Natarajan M and Aravindan N: Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53-NFκB crosstalk. Phytochemistry. 167(112078)2019.PubMed/NCBI View Article : Google Scholar | |
Beppu F, Niwano Y, Tsukui T, Hosokawa M and Miyashita K: Single and repeated oral dose toxicity study of fucoxanthin (FX), a marine carotenoid, in mice. J Toxicol Sci. 34:501–510. 2009.PubMed/NCBI View Article : Google Scholar | |
Hashimoto T, Ozaki Y, Mizuno M, Yoshida M, Nishitani Y, Azuma T, Komoto A, Maoka T, Tanino Y and Kanazawa K: Pharmacokinetics of fucoxanthinol in human plasma after the oral administration of kombu extract. Br J Nutr. 107:1566–1569. 2012.PubMed/NCBI View Article : Google Scholar | |
Dang TT, Bowyer MC, Van Altena IA and Scarlett CJ: Comparison of chemical profile and antioxidant properties of the brown algae. Int J Food Sci Technol. 53:174–181. 2008. | |
Guan B, Chen K, Tong Z, Chen L, Chen Q and Su J: Advances in fucoxanthin research for the prevention and treatment of inflammation-related diseases. Nutrients. 14(4768)2022.PubMed/NCBI View Article : Google Scholar | |
Mumu M, Das A, Emran TB, Mitra S, Islam F, Roy A, Karim MM, Das R, Park MN, Chandran D, et al: Fucoxanthin: A promising phytochemical on diverse pharmacological targets. Front Pharmacol. 13(929442)2022.PubMed/NCBI View Article : Google Scholar | |
Ishikawa C, Tafuku S, Kadekaru T, Sawada S, Tomita M, Okudaira T, Nakazato T, Toda T, Uchihara JN, Taira N, et al: Anti-adult T-cell leukemia effects of brown algae fucoxanthin and its deacetylated product, fucoxanthinol. Int J Cancer. 123:2702–2712. 2008.PubMed/NCBI View Article : Google Scholar | |
Liu CL, Liang AL and Hu ML: Protective effects of fucoxanthin against ferric nitrilotriacetate-induced oxidative stress in murine hepatic BNL CL.2 cells. Toxicol In Vitro. 25:1314–1319. 2011.PubMed/NCBI View Article : Google Scholar | |
Liu CL, Lim YP and Hu ML: Fucoxanthin enhances cisplatin-induced cytotoxicity via NFκB-mediated pathway and downregulates DNA repair gene expression in human hepatoma HepG2 cells. Mar Drugs. 11:50–66. 2013.PubMed/NCBI View Article : Google Scholar | |
Wang SK, Li Y, White WL and Lu J: Extracts from New Zealand Undaria pinnatifida containing fucoxanthin as potential functional biomaterials against cancer in vitro. J Funct Biomater. 5:29–42. 2014.PubMed/NCBI View Article : Google Scholar | |
Martin LJ: Fucoxanthin and its metabolite fucoxanthinol in cancer prevention and treatment. Mar Drugs. 13:4784–4798. 2015.PubMed/NCBI View Article : Google Scholar | |
Takahashi K, Hosokawa M, Kasajima H, Hatanaka K, Kudo K, Shimoyama N and Miyashita K: Anticancer effects of fucoxanthin and fucoxanthinol on colorectal cancer cell lines and colorectal cancer tissues. Oncol Lett. 10:1463–1467. 2015.PubMed/NCBI View Article : Google Scholar | |
Terasaki M, Kubota A, Kojima H, Maeda H, Miyashita K, Kawagoe C, Mutoh M and Tanaka T: Fucoxanthin and colorectal cancer prevention. Cancers (Basel). 13(2379)2021.PubMed/NCBI View Article : Google Scholar | |
Ming JX, Wang ZC, Huang Y, Ohishi H, Wu RJ, Shao Y, Wang H, Qin MY, Wu ZL, Li YY, et al: Fucoxanthin extracted from Laminaria japonica inhibits metastasis and enhances the sensitivity of lung cancer to Gefitinib. J Ethnopharmacol. 265(113302)2021.PubMed/NCBI View Article : Google Scholar | |
Malhão F, Macedo AC, Costa C, Rocha E and Ramos AA: Fucoxanthin holds potential to become a drug adjuvant in breast cancer treatment: Evidence from 2D and 3D cell cultures. Molecules. 26(4288)2021.PubMed/NCBI View Article : Google Scholar | |
Ye GL, Du DL, Jin LJ and Wang LL: Sensitization of TRAIL-resistant cervical cancer cells through combination of TRAIL and fucoxanthin treatments. Eur Rev Med Pharmacol Sci. 21:5594–5601. 2017.PubMed/NCBI View Article : Google Scholar | |
Hidalgo M, Cascinu S, Kleeff J, Labianca R, Löhr JM, Neoptolemos J, Real FX, Van Laethem JL and Heinemann V: Addressing the challenges of pancreatic cancer: Future directions for improving outcomes. Pancreatology. 15:8–18. 2015.PubMed/NCBI View Article : Google Scholar | |
Jiang PH, Motoo Y, Sawabu N and Minamoto T: Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells. World J Gastroenterol. 12:1597–1602. 2006.PubMed/NCBI View Article : Google Scholar | |
Gradiz R, Silva HC, Carvalho L, Botelho MF and Mota-Pinto A: MIA PaCa-2 and PANC-1-pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci Rep. 6(21648)2016.PubMed/NCBI View Article : Google Scholar | |
Ghasemi M, Turnbull T, Sebastian S and Kempson I: The MTT assay: Utility, limitations, pitfalls, and interpretation in bulk and single-cell analysis. Int J Mol Sci. 22(12827)2021.PubMed/NCBI View Article : Google Scholar | |
Cho YS and Cho-Chung YS: Antisense protein kinase A RIalpha acts synergistically with hydroxycamptothecin to inhibit growth and induce apoptosis in human cancer cells: Molecular basis for combinatorial therapy. Clin Cancer Res. 9:1171–1178. 2003.PubMed/NCBI | |
Bocci G, Fioravanti A, Orlandi P, Bernardini N, Collecchi P, Del Tacca M and Danesi R: Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells. Br J Cancer. 93:319–330. 2005.PubMed/NCBI View Article : Google Scholar | |
Yeo D, Huynh N, Beutler JA, Christophi C, Shulkes A, Baldwin GS, Nikfarjam M and He H: Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases. Cancer Lett. 346:264–272. 2014.PubMed/NCBI View Article : Google Scholar | |
Rathos MJ, Joshi K, Khanwalkar H, Manohar SM and Joshi KS: Molecular evidence for increased antitumor activity of gemcitabine in combination with a cyclin-dependent kinase inhibitor, P276-00 in pancreatic cancers. J Transl Med. 10(161)2012.PubMed/NCBI View Article : Google Scholar | |
Wu S, Guo J, Wei W, Zhang J, Fang J and Beebe SJ: Enhanced breast cancer therapy with nsPEFs and low concentrations of gemcitabine. Cancer Cell Int. 14(98)2014.PubMed/NCBI View Article : Google Scholar | |
Kornmann M, Butzer U, Blatter J, Beger HG and Link KH: Pre-clinical evaluation of the activity of gemcitabine as a basis for regional chemotherapy of pancreatic and colorectal cancer. Eur J Surg Oncol. 26:583–587. 2000.PubMed/NCBI View Article : Google Scholar | |
Hernández P, Olivera P, Dueñas-Gonzalez A, Pérez-Pastenes MA, Zárate A, Maldonado V and Meléndez-Zajgla J: Gemcitabine activity in cervical cancer cell lines. Cancer Chemother Pharmacol. 48:488–492. 2001.PubMed/NCBI View Article : Google Scholar | |
Yong-Xian G, Xiao-Huan L, Fan Z and Guo-Fang T: Gemcitabine inhibits proliferation and induces apoptosis in human pancreatic cancer PANC-1 cells. J Cancer Res Ther. 12 (Suppl):S1–S4. 2016.PubMed/NCBI View Article : Google Scholar | |
Iwase R, Haruki K, Fujiwara Y, Furukawa K, Shiba H, Uwagawa T, Misawa T, Ohashi T and Yanaga K: Combination chemotherapy of nafamostat mesylate with gemcitabine for gallbladder cancer targeting nuclear factor-κB activation. J Surg Res. 184:605–612. 2013.PubMed/NCBI View Article : Google Scholar | |
Rousseau EJ, Davison AJ and Dunn B: Protection by beta-carotene and related compounds against oxygen-mediated cytotoxicity and genotoxicity: Implications for carcinogenesis and anticarcinogenesis. Free Radic Biol Med. 13:407–433. 1992.PubMed/NCBI View Article : Google Scholar | |
Bertram JS and Vine AL: Cancer prevention by retinoids and carotenoids: Independent action on a common target. Biochim Biophys Acta. 1740:170–178. 2005.PubMed/NCBI View Article : Google Scholar | |
Pádua D, Rocha E, Gargiulo D and Ramos A: Bioactive compounds from brown seaweeds: Phloroglucinol, fucoxanthin and fucoidan as promising therapeutic agents against breast cancer. Phytochem Lett. 14:91–98. 2015. | |
Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS, Han JA, Yim SV, Chang K, Kwon YG, et al: Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Mol Cells. 16:97–105. 2003.PubMed/NCBI | |
Campo GM, Avenoso A, Campo S, D'Ascola A, Traina P, Samà D and Calatroni A: The antioxidant effect exerted by TGF-1beta-stimulated hyaluronan production reduced NF-kB activation and apoptosis in human fibroblasts exposed to FeSo4 plus ascorbate. Mol Cell Biochem. 311:167–177. 2008.PubMed/NCBI View Article : Google Scholar | |
Kumar SR, Hosokawa M and Miyashita K: Fucoxanthin: A marine carotenoid exerting anti-cancer effects by affecting multiple mechanisms. Mar Drugs. 11:5130–5147. 2013.PubMed/NCBI View Article : Google Scholar | |
Fan M, Nath AK, Tang Y, Choi YJ, Debnath T, Choi EJ and Kim EK: Investigation of the anti-prostate cancer properties of marine-derived compounds. Mar Drugs. 16(160)2018.PubMed/NCBI View Article : Google Scholar | |
Asai A, Sugawara T, Ono H and Nagao A: Biotransformation of fucoxanthinol into amarouciaxanthin A in mice and HepG2 cells: Formation and cytotoxicity of fucoxanthin metabolites. Drug Metab Dispos. 32:205–211. 2004.PubMed/NCBI View Article : Google Scholar | |
Maeda H, Hosokawa M, Sashima T, Takahashi N, Kawada T and Miyashita K: Fucoxanthin and its metabolite, fucoxanthinol, suppress adipocyte differentiation in 3T3-L1 cells. Int J Mol Med. 18:147–152. 2006.PubMed/NCBI | |
Eid SY, Althubiti MA, Abdallah ME, Wink M and El-Readi MZ: The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes. Phytomedicine. 77(153280)2020.PubMed/NCBI View Article : Google Scholar | |
Baker CH, Banzon J, Bollinger JM, Stubbe J, Samano V, Robins MJ, Lippert B, Jarvi E and Resvick R: 2'-Deoxy-2'-methylenecytidine and 2'-deoxy-2',2'-difluorocytidine 5'-diphosphates: Potent mechanism-based inhibitors of ribonucleotide reductase. J Med Chem. 34:1879–1884. 1991.PubMed/NCBI View Article : Google Scholar | |
Jones RM, Kotsantis P, Stewart GS, Groth P and Petermann E: BRCA2 and RAD51 promote double-strand break formation and cell death in response to gemcitabine. Mol Cancer Ther. 13:2412–2421. 2014.PubMed/NCBI View Article : Google Scholar | |
Li Y, Wang LR, Chen J, Lou Y and Zhang GB: First-line gemcitabine plus cisplatin in nonsmall cell lung cancer patients. Dis Markers. 2014(960458)2014.PubMed/NCBI View Article : Google Scholar | |
Ke Z, Fu T, Wang X, Xuan M, Yin H, Zhou J, Liu Y and Liang A: CHK1 inhibition overcomes gemcitabine resistance in non-small cell lung cancer cell A549. Res Sq, 2022. | |
Du L, Lyle CS, Obey TB, Gaarde WA, Muir JA, Bennett BL and Chambers TC: Inhibition of cell proliferation and cell cycle progression by specific inhibition of basal JNK activity: Evidence that mitotic Bcl-2 phosphorylation is JNK-independent. J Biol Chem. 279:11957–11966. 2004.PubMed/NCBI View Article : Google Scholar | |
Bildstein L, Pili B, Marsaud V, Wack S, Meneau F, Lepêtre-Mouelhi S, Desmaële D, Bourgaux C, Couvreur P and Dubernet C: Interaction of an amphiphilic squalenoyl prodrug of gemcitabine with cellular membranes. Eur J Pharm Biopharm. 79:612–620. 2011.PubMed/NCBI View Article : Google Scholar | |
Mc Gee MM: Targeting the mitotic catastrophe signaling pathway in cancer. Mediators Inflamm. 2015(146282)2015.PubMed/NCBI View Article : Google Scholar | |
Montano R, Thompson R, Chung I, Hou H, Khan N and Eastman A: Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: Cell cycle perturbation and impact of administration schedule in vitro and in vivo. BMC Cancer. 13(604)2013.PubMed/NCBI View Article : Google Scholar | |
Guo JR, Chen QQ, Lam CW, Wang CY, Wong VK, Chang ZF and Zhang W: Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells. Sci Rep. 6(37250)2016.PubMed/NCBI View Article : Google Scholar | |
Kajstura M, Halicka HD, Pryjma J and Darzynkiewicz Z: Discontinuous fragmentation of nuclear DNA during apoptosis revealed by discrete ‘sub-G1’ peaks on DNA content histograms. Cytometry A. 71:125–131. 2007.PubMed/NCBI View Article : Google Scholar | |
Haddad NF, Teodoro AJ, Leite de Oliveira F, Soares N, de Mattos RM, Hecht F, Dezonne RS, Vairo L, Goldenberg RC, Gomes FC, et al: Lycopene and beta-carotene induce growth inhibition and proapoptotic effects on ACTH-secreting pituitary adenoma cells. PLoS One. 8(e62773)2013.PubMed/NCBI View Article : Google Scholar | |
Milani A, Basirnejad M, Shahbazi S and Bolhassani A: Carotenoids: Biochemistry, pharmacology and treatment. Br J Pharmacol. 174:1290–1324. 2017.PubMed/NCBI View Article : Google Scholar | |
Das SK, Hashimoto T, Shimizu K, Yoshida T, Sakai T, Sowa Y, Komoto A and Kanazawa K: Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. Biochim Biophys Acta. 1726:328–335. 2005.PubMed/NCBI View Article : Google Scholar | |
Yu RX, Hu XM, Xu SQ, Jiang ZJ and Yang W: Effects of fucoxanthin on proliferation and apoptosis in human gastric adenocarcinoma MGC-803 cells via JAK/STAT signal pathway. Eur J Pharmacol. 657:10–19. 2011.PubMed/NCBI View Article : Google Scholar | |
Koklesova L, Liskova A, Samec M, Buhrmann C, Samuel SM, Varghese E, Ashrafizadeh M, Najafi M, Shakibaei M, Büsselberg D, et al: Carotenoids in cancer apoptosis-the road from bench to bedside and back. Cancers (Basel). 12(2425)2020.PubMed/NCBI View Article : Google Scholar | |
García-Olmo DC, Riese HH, Escribano J, Ontañón J, Fernandez JA, Atiénzar M and García-Olmo D: Effects of long-term treatment of colon adenocarcinoma with crocin, a carotenoid from saffron (Crocus sativus L.): An experimental study in the rat. Nutr Cancer. 35:120–126. 1999.PubMed/NCBI View Article : Google Scholar | |
Eid SY, El-Readi MZ and Wink M: Carotenoids reverse multidrug resistance in cancer cells by interfering with ABC-transporters. Phytomedicine. 19:977–987. 2012.PubMed/NCBI View Article : Google Scholar | |
Kwon M, Jung H, Nam GH and Kim IS: The right timing, right combination, right sequence, and right delivery for cancer immunotherapy. J Control Release. 331:321–334. 2021.PubMed/NCBI View Article : Google Scholar |