Proanthocyanidin: An interesting option as cisplatinalternative in solid tumor treatment

Abstract

Cisplatin is an approved chemotherapeutic for treating many solid tumors, but it can cause toxicities e.g. nephrotoxicity, which restrict its application. Therefore, researchers are looking for safer and more effective cisplatinalternatives. Although proanthocyanidins’ protective effects against many cisplatin-induced toxicities have been published and their anticancer activity has been investigated in some research papers, their anticancer efficacy compared to cisplatin has not been investigated yet, making them an interesting candidate. So, we aimed to evaluate the therapeutic efficacy of grape seed proanthocyanidin extract (GSE) in treating solid tumor-bearing mice compared to cisplatin. Sixty adult female Swiss albino mice were grouped (ten mice/group): Normal, EAC (1x106 Ehrlich ascites carcinoma cells/mouse/once; subcutaneous), EAC+Cisplatin (3.5 mg/kg/once, intraperitoneal), and EAC+50 or 75 or 100 mg/kg/day, oral for 13 days). Blood, livers, and tumors were obtained, and tumor weights, volumes, and hepatic concentrations of malondialdehyde, glutathione, superoxide dismutase, catalase, and nitric oxide were estimated. Serum albumin, alanine aminotransferase, aspartate aminotransferase, cholesterol, triglycerides, lactate dehydrogenase, and creatine phosphokinase were assessed. Survival and lifespan indexes were calculated. GSE treatment boosted antioxidant levels, improved biochemical changes, protected liver and heart tissues from tumor-induced damage, reduced tumor size, and increased median survival time (MST) and percentage increase in lifespan (%ILS). GSE at 100 mg/kg was a more effective antitumor than cisplatin. Finally, our results recommend GSE as a potentially effective cisplatin-therapeutic alternative against solid tumors after more research.

Keywords

• Antitumor
• Cisplatin
• Efficacy
• Protective
• Heart
• Lifespan
• Liver
• Survival

References

1. [1] Hossain IA, Khanam JA, Jesmin M, Ali MM. Antineoplastic activity of N-(2-hydroxybenzylidene) 2′ hydroxypheny limine aqua nickel (II) complex [Ni(H2O)HHP] on Ehrlich Ascites Carcinoma (EAC) in Swiss albino mice. Exp Toxicol Pathol. 2016;68(1):15-25. https://doi.org/10.1016/j.etp.2015.09.003.
2. [2] El Sadda RR, Elshahawy ZR, Saad EA. Biochemical and pathophysiological improvements in rats with thioacetamide induced-hepatocellular carcinoma using aspirin plus vitamin C. BMC cancer. 2023;23(1):175. https://doi.org/10.1186/s12885-023-10644-5.
3. [3] El-Aassar MR, Saad EA, Habib SA, Waly HM. Loading of some quinoxaline derivatives in poly (l-lactic) acid/Pluronic® F-127 nanofibers enhances their anticancer efficiency and induces a p53 and p21 apoptotic-signaling pathway. Colloids Surf B: Biointerfaces. 2019;183C:110444. https://doi.org/10.1016/j.colsurfb.2019.110444.
4. [4] El-Emshaty HM, Saad EA, Gouida MS, Elshahawy ZR. Associations between CD133, CK19 and G2/M in cirrhotic HCV (genotype-4) patients with or without accompanying tumor. Biocell. 2018;42(2):55-60. https://doi.org/10.32604/biocell.2018.07009.
5. [5] WHO (World Health Organization)-Cancer 2022. https:// www.who.int / news-room/fact-sheets/detail/cancer, (accessed on 3 February 2022).
6. [6] Saad EA, Elsayed SA, Hassanien MM, Al-Adl MS. The new iron(III) 3-oxo-N-(pyridin-2-yl)butanamide complex promotes Ehrlich solid tumor regression in mice via induction of apaptosis. Appl Organomet Chem. 2020;34(1):e5282. https://doi.org/10.1002/aoc.5282.
7. [7] Hassona SM, Saad EA, Kiwan HA, Hassanien MM. Palladium (II) Schiff base complex arrests cell cycle at early stages, induces apoptosis, and reduces Ehrlich solid tumor burden: a new candidate for tumor therapy. Invest New Drugs. 2022;40(4):681-689. https://doi.org/10.1007/s10637-022-01234-6.
8. [8] Prater E (2024): Global cancer rates are expected to rise 77% by 2050, the WHO warns. From aging to alcohol, here’s why. February 1, 2024. https://fortune.com/well/2024/02/01/global-cancer-rates-rise-world-health-organization-aging-alcohol/

9. [9] Medhat D, Hussein J, El-Naggar ME, Attia MF, Anwar M, Latif YA, Booles HF, Morsy S, Farrag AR, Khalil WKB, El-Khayat Z. Effect of Au-dextran NPs as anti-tumor agent against EAC and solid tumor in mice by biochemical evaluations and histopathological investigations. Biomed Pharmacother. 2017;91:1006-1016. https://doi.org/10.1016/j.biopha.2017.05.043.
10. [10] Karmaker I, Dolai N, Kumar RBS, Kar B, Roy SN, Haldar PK. Antitumor activity and antioxidant property of Curcuma caesia against Ehrlich’s ascites carcinoma bearing mice. Pharm Biol. 2013;51(6):753-759. https://doi.org/10.3109/13880209.2013.764538.
11. [11] Naeem A, Hu P, Yang M, Zhang J, Liu Y, Zhu W, Zheng Q. Natural products as anticancer agents: current status and future perspectives. Molecules. 2022;27(23):8367. https:// doi.org /10.3390 / molecules27238367.
12. [12] Swellam M, Saad EA, Sabry S, Denewer A, Abdel Malak C, Abouzid A. Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay. J Genet Eng Biotechnol. 2021;19(1):54. https://doi.org/10.1186/s43141-021-00154-x.
13. [13] Kong F-T, He C-X, Kong F-L, Han S-F, Kong S, Han W-Q, Yang L-X. Grape seed procyanidins inhibit the growth of breast cancer MCF-7 cells by down-regulation the EGFR/VEGF/MMP9 pathway. Nat Product Commun. 2021;16(2). http://dx.doi.org/10.1177/1934578X21991691.
14. [14] Saleh N, Allam T, Korany RMS, Abdelfattah AM, Omran AM, Abd Eldaim MA, Hassan AM, El-Borai NB. Protective and therapeutic efficacy of hesperidin versus cisplatin against Ehrlich Ascites Carcinoma-induced renal damage in mice. Pharmaceuticals (Basel). 2022;15(3):294. https://doi.org/10.3390/ph15030294.
15. [15] Aldubayan MA, Elgharabawy RM, Ahmed AS, Tousson E. Antineoplastic activity and curative role of Avenanthramides against the growth of Ehrlich solid tumors in mice. Oxid Med Cell Longev. 2019;2019:5162687. https://doi.org/10.1155/2019/5162687.
16. [16] Saad EA, El-Demerdash RS, Abd ElFattah ME. Mesenchymal stem cells are more effective than captopril in reverting cisplatin- induced nephropathy. Biocell. 2019;43(2):73-79. https://doi.org/ 10.32604/ biocell.2019.07020.
17. [17] Saad EA, Kiwan HA, Hassanien MM, Al-Adl HE. Synthesis, characterization, and antitumor activity of a new iron-rifampicin complex: A novel prospective antitumor drug. J Drug Deliv Sci Technol. 2020;57:101671. https://doi.org/10.1016/j.jddst.2020.101671.
18. [18] Al-Rasheed NM, El-Masry TA, Tousson E, Hassan HM, Al-Ghadeer A. Hepatic protective effect of grape seed proanthocyanidin extract against Gleevec-induced apaptosis, liver injury and Ki67 alterations in rats. Braz J Pharm Sci. 2018;54(2):e17391. https://doi.org/10.1590/s2175-97902018000217391.
19. [19] Rasmussen SE, Frederiksen H, Struntze Krogholm K, Poulsen L. Dietary proanthocyanidins: occurrence, dietary intake, bioavailability, and protection against cardiovascular disease. Mol Nutr Food Res. 2005;49(2):159-174. https://doi.org/10.1002/mnfr.200400082.
20. [20] Terra X, Montagut G, Bustos M, Llopiz N, Ardevol A, Blade C, Fernández-Larrea J, Pujadas G, Salvadó J, Arola L, Blay M. Grape-seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet. J Nutr Biochem. 2009;20(3):210-218. https://doi.org/10.1016/j.jnutbio.2008.02.005.
21. [21] Aghbali A, Hosseini SV, Delazar A, Gharavi NK, Shahneh FZ, Orangi M, Bandehagh A, Baradaran B. Induction of apaptosis by grape seed extract (Vitis vinifera) in oral squamous cell carcinoma. Bos J Basic Med Sci. 2013;13(3):186-191. https://doi.org/10.17305/bjbms.2013.2360.
22. [22] Longchar A, Prasad SB. Biochemical changes associated with ascorbic acid-cisplatin combination therapeutic efficacy and protective effect on cisplatin-induced toxicity in tumor-bearing mice. Toxicol Rep. 2015;2:489–503. https://doi.org/10.1016/j.toxrep.2015.01.017.
23. [23] Saad EA, Hassanien MM, El-lban FW. Nickle (II) diacetyl monoxime-2-pyridyl hydrazine complex can inhibit Ehrlish solid tumor growth in mice: A potential new antitumor drug. Biochem Biophys Res Commun. 2017;484(3):579-585. https://doi.org/10.1016/j.bbrc.2017.01.137.
24. [24] Aboseada HA, Hassanien MM, El-Sayed IH, Saad EA. Schiff base 4-ethyl-1-(pyridine-2-yl) thiosemicarbazide up-regulates the antioxidant status and inhibits the progression of Ehrlish solid tumor in mice. Biochem Biophys Res Commun. 2021;573:42-47. https://doi.org/10.1016/j.bbrc.2021.07.102.
25. [25] Saad EA, Zahran F, El-Ablack FZ, Eleneen A. A Newly synthesized derivative and a natural parent molecule: Which would be more beneficial as a future antitumor candidate? Docking and in vivo study. Appl Biochem Biotechnol. 2022;194:5386-5402. https:// doi.org /10.1007 /s12010-022-04037-w.
26. [26] Yang CS, Wang H. Mechanistic issues concerning cancer prevention by tea catechins. Mol Nutr Food Res. 2011;55(6):819-831. https://doi.org/10.1002/mnfr.201100036.
27. [27] Abd Eldaim MA, Tousson E, El Sayed IE, Abd El-Aleim AH, Elsharkawy HN. Grape seeds proanthocyanidin extract ameliorates Ehrlish solid tumor induced renal tissue and DNA damage in mice. Biomed Pharmacother. 2019;115:108908. https://doi.org/10.1016/j.biopha.2019.108908.
28. [28] Donenko FV, Kabieva AO, Moroz LV. The modelling of the growth of Ehrlish carcinoma and Teratoma T-36 with ascetic fluid and tumor-cell dialysate. Biull Eksp Biol Med. 1992;114(8):193-195.
29. [29] Prasad R, Vaid M, Katiyar SK. Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/AKt pathway. PLoS One. 2012;7(8):e43064.https://doi.org/10.1371/journal.pone.0043064.
30. [30] Dinicola SA, Cucina A, Pasqualato A, Proietti S, D'Anselmi F. Apoptosis-inducing factor and caspase-dependent apoptotic pathways triggered by different grape seed extracts on human colon cancer cell line Caco-2. Br J Nutr. 2010;104(6):824-832. https://doi.org/10.1017/s0007114510001522.
31. [31] Elsadek MF, El-Din MME, Ahmed BM. Evaluation of anticarcinogenic and antioxidant properities of Eruca sativa extracts versus Ehrlich ascites carcinoma in mice. J King Saud Univ Sci. 2021;33(4):101435. https://doi.org/10.1016/J.JKSUS.2021.101435.
32. [32] Sur P, Bag SP, Sur B, Khanam JA. Chloroaceto hydroxamic acid as antitumor agent against Ehrlich ascites carcinoma in mice. Neoplasma. 1997;44(3):197-201.
33. [33] Kathiriya A, Das K, Kumar EP, Mathai KB. Evaluation of antitumor and antioxidant activity of Oxalis corniculata Linn. against Ehrlish Ascites Carcinoma on mice. Iran J Cancer Prev. 2010;3(4):157-165.
34. [34] Gaspar BL, Sharma P, Das R. Anemia in malignancies: pathogenetic and diagnostic considerations. Hematology. 2015;20(1):18-25. https://doi.org/10.1179/1607845414y.0000000161.
35. [35] Rajkapoor B, Jayakar B, Murugesh N. Antitumor activity of Indigofera aspalathoides on Ehrlich ascites carcinoma in mice. Indian J Pharmacol. 2004;36(1):38-40.
36. [36] Strasenburg W, Jóźwicki J, Durślewicz J, Kuffel B, Kulczyk MP, Kowalewski A, Grzanka D, Drewa T, Adamowicz J. Tumor cell-induced platelet aggregation as an emerging therapeutic target for cancer therapy. Front Oncol. 2022;12:909767. https://doi.org/10.3389/fonc.2022.909767.
37. [37] Islam K, Ali SMM, Jesmin M, Khanam JA. In vivo anticancer activities of benzophenone semicarbazone against Ehrlish ascites carcinoma cells in Swiss Albino mice. Cancer Biol Med. 2012;9(4):242-247. https://doi.org/10.7497/j.issn.2095-3941.2012.04.004.
38. [38] Dolai N, Karmakar I, Kumar SRB, Kar B, Bala A, Haldar PK. Evaluation of antitumor activity and in vivo antioxidant status of Anthocephalus cadamba on Ehrlich ascites carcinoma treated mice. J Ethnopharmacol. 2012;142(3):865–870. https://doi.org/10.1016/j.jep.2012.05.050.
39. [39] Ozaslan M, Karagoz ID, Kilic IH, Guldur ME. Ehrlish ascites carcinoma. Afr J Biotechnol. 2011;10(13):2375-2378. http://www.academicjournals.org/AJB10.5897/AJBx10.017.
40. [40] Raju A, Arockiasamy JMC. Modulatory effects of Drosera indica L on EAC induced metabolic changes in mice. Mol Clin Pharmacol. 2013;4(1):59-64.
41. [41] Saad EA, Habib SA, Eltabeey M. Diagnostic performance of AFP, autotoxin and collagen IV and their combinations for non-invasive assessment of hepatic fibrosis staging in liver fibrosis patients associated with chronic HCV. Int J Pharm Qual Assur. 2017;8:165–173. https://doi.org/10.25258/ijpqa.v8i04.10542.
42. [42] Gupta M, Mazumder UK, Kumar RS, Kumar TS. Antitumor activity and antioxidant role of Bauhinia racemosa against Ehrlich ascites carcinoma in Swiss albino mice. Acta Pharmacolo Sin. 2004;25(8):1070-1076.
43. [43] Salem FS, Badr MOT, Neamat-Allah ANF. Biochemical and pathological studies on the effects of levamisole and chlorambucil on Ehrlish ascites carcinoma-bearing mice. Vet Ital. 2011;74(1):89-95.
44. [44] Ali DA, Badr El-Din NK, Abou-El-magd RF. Antioxidant and hepatoprotective activities of grape seeds and skin against Ehrlich solid tumor induced oxidative stress in mice. Egypt J Basic Appl Sci. 2015;2(2):98-109. https://doi.org/10.1016/j.ejbas.2015.02.003.
45. [45] Abdeen SHF, Edrees GMF, Shalaby EMI. Protective effect of proanthocyanidin on physiological and immunological disorders induced by Ehrlich Ascites carcinoma (EAC). Middle East J Appl Sci. 2018;8(2):583-593.
46. [46] Bovi APD, Marciano F, Mandato C, Siano MA, Savoia M, Vajro P. Oxidative stress in non-alcoholic fatty liver disease. Front Med. 2021;8:595371. https://doi.org/10.3389/fmed.2021.595371.
47. [47] Pandya NB, Tigari P, Dupadahalli K, Kamurthy H, Nadendla RR. Antitumor and antioxidant status of Terminalia catappa against Ehrlich ascites carcinoma in Swiss albino mice. Indian J Pharmacol. 2013;45(5):464-469. https://doi.org/10.4103/0253-7613.117754.
48. [48] Basal OA, Zahran RF, Saad EA. Rifampicin efficacy against doxorubicin-induced cardiotoxicity in mice. Egypt Heart J. 2023;75(1):73. https://doi.org/10.1186/s43044-023-00403-z.
49. [49] El-Shahat RA, El-Demerdash RS, El Sherbini ES, Saad EA. HCl-induced acute lung injury: a study of the curative role of mesenchymal stem/stromal cells and cobalt protoporphyrin. J Genet Eng Biotechnol. 2021;19(1):41. https:// doi. org/ 10. 1186/s43141- 021- 00139-w.
50. [50] Habib SA, Saad EA, Al-Mutairi FM, Alalawy AI, Sayed MH, El-Sadda RR. Up-regulation of antioxidant status in chronic renal failure rats treated with mesenchymal stem cells and hematopoietic stem cells. Pak J Biol Sci. 2020;23(6):820–828. https:// doi. org/ 10.3923/ pjbs. 2020. 820. 828.
51. [51] Shosha MI, El-Ablack FZ, Saad EA. Glycine protects against doxorubicin-induced heart toxicity in mice. Amino Acids. 2023;55(5):679-693. https:// doi. org/10.1007/s00726-023-03261-w.
52. [52] Zahran F, Saad EA, El-Ablack FZ, Abo Eleneen AM. New synthetic flavonoid with in vitro antitumor activity. Int J Sci Eng Res. 2019;10(1):606-609.
53. [53] Saad EA, Hassanien MM, Elneely EA. Iron (III) diacetyl monoxime-2-hydrazinopyridine complex: A new prospective antitumor drug. Appl Organomet Chem. 2017;31(9):e3684. http://dx.doi.org/10.1002/aoc.3684.
54. [54] Abd El Azeem RA, Zedan MM, Saad EA, Mutawi TM, Attia ZR. Single-nucleotide polymorphisms (SNPS) of antioxidant enzymes SOD2 and GSTP1 genes and SLE risk and severity in an Egyptian pediatric population. Clin Biochem. 2021;88(C):37-42. https://doi.org/10.1016/j.clinbiochem.2020.11.010.
55. [55] Zahran RF, Geba ZM, Tabll AA, Mashaly MM. Therapeutic potential of a novel combination of Curcumin with Sulfamethoxazole against carbon tetrachloride-induced acute liver injury in Swiss albino mice. J Genet Eng Biotechnol. 2020;18(1):13. https://doi.org/10.1186/s43141-020-00027-9.
56. [56] Saad EA, El-Gayar HA, El-Demerdash RS, Radwan KH. Frankincense administration antagonizes adenine-induced chronic renal failure in rats. Pharmacogn Mag. 2018;14(58):634–640. http://dx.doi.org/10.4103/pm.pm_271_18.
57. [57] Mahmoud EA. Anticarcinogenic effect of grape seeds extract against Ehrlich ascites tumour in mice. Glob Vet. 2015;15(2):207-214. https:// doi. org/10.5829/idosi.gv.2015.15.02.96200.
58. [58] Habib SA, Saad EA, Elsharkawy AA, Attia ZR. Pro-inflammatory adipocytokines, oxidative stress, insulin, Zn and Cu: Interrelations with obesity in Egyptian non-diabetic obese children and adolescents. Adv Med Sci. 2015;60(2):179-185. https://doi.org/10.1016/j.advms.2015.02.002.
59. [59] Mintz J, Vedenko A, Rosete O, Shah K, Goldstein G, Hare JM, Ramasamy R, Arora H. Current advances of nitric oxide in cancer and anticancer therapeutics. Vaccines. 2021;9(2):94. https://doi.org/10.3390/vaccines9020094.
60. [60] Luanpitpong S, Chanvorachote P. Nitric oxide and aggressive behavior of lung cancer cells. Anticancer Res. 2015;35(9):4585-4592.
61. [61] Wang M, Zhu L, Zhang S, Lou Y, Zhao S, Tan Q, He L, Du M. A copper(II) phthalocyanine-based metallo-covalent organic framework decorated with silver nanoparticle for sensitively detecting niric oxide released from cancer cells. Sens Actuators B: Chem. 2021;338:129826. https://doi.org/10.1016/J.SNB.2021.129826.
62. [62] Samudrala PK, Augustine BB, Kasala ER, Bodduluru LN, Barua C, Lahkar M. Evaluation of antitumor activity and antioxidant status of Alternanthera brasiliana against Ehrlich ascites carcinoma in Swiss albino mice. Pharmacogn Res. 2015;7(1):66-73. https://doi.org/10.4103/0974-8490.147211.
63. [63] Elshahawy ZR, Saad EA, El-Sadda RR. Synergistic impacts of rifampicin and doxorubicin against thioacetamide-induced hepatocellular carcinoma in rats. Liver Res. 2023;7:352-360. https: // doi.org /10.1016 / j.livres.2023.11.005.
64. [64] Almajwal AM, Elsadek MF. Lipid-lowering and hepatoprotective effects of Vitis vinifera dried seeds on paracetamol-induced hepatotoxicity in rats. Nutr Res Pract. 2015;9(1):37-42. https://doi.org/10.4162/nrp.2015.9.1.37.
65. [65] Chis IC, Ungureanu MI, Marton A, Simedrea R, Muresan A, Postescu ID, Decea N. Antioxidant effects of a grape seed extract in a rat model of diabetes mellitus. Diabetes Vasc Dis Res. 2009;6(3):200-204. https://doi.org/10.1177/1479164109336692.
66. [66] Djakpo DK, Wang ZQ, Shrestha M. The significance of transaminase ratio (AST/ALT) in acute myocardial infarction. Arch Med Sci – Atheroscler Dis. 2020;5:e279–e283. https:// doi.org /10.5 114 / amsad.2020. 103028.
67. [67] Ibrahim MA, Bakhaat GA, Tammam HG, Mohamed RM, El-Naggar SA. Cardioprotective effect of green tea extract and vitamin E on Cisplatin-induced cardiotoxicity in mice: Toxicological, histological and immunohistochemical studies. Biomed Pharmacother. 2019;113:108731. https://doi.org/10.1016/j.biopha.2019.108731.
68. [68] Maghamiour N, Safaie N. High Creatine Kinase (CK)-MB and Lactate Dehydrogenase in the absence of myocardial injury or infraction: A case report. J Cardiovasc Thorac Res. 2014;6(1):69-70. https://doi.org/10.5681/jcvtr.2014.014.
69. [69] Fadillioglu E, Erdogan H. Effects of erdosteine treatment against doxorubicin-induced toxicity through erythrocyte and plasma oxidant/antioxidant status in rats. Pharmacol Res. 2003;47(4):317-322. https://doi.org/10.1016/s1043-6618(03)00010-0
70. [70] Hassanien MM, Saad EA, Radwan KH. Antidiabetic activity of cobalt-quercetin complex: A new potential candidate for diabetes treatment. J Appl Pharmaceut Sci. 2020;10(12):44-52. http://dx.doi.org/10.7324/JAPS.2020.101206.
71. [71] Ghosh MN. Fundamentals of Experimental Pharmacology, Second ed., Scientific Book Agency, Calcutta, India, 1984.
72. [72] MacLimans WF, Davis EV, Glover FL, Rake GW. The submerged culture of mammalian cells: the spinner culture. J Immunol. 1957;79:428-436.
73. [73] Dacie JV, Lewis SM. Practical Hematologty, Churchill-Livingstone, New York; 1984; pp. 152–178.
74. [74] D’Amour FF, Blood FR, Belden DA, The manual for Laboratory Work in mammalian Physiology, The University of Chicago Press, Chicago, 1965, pp. 148–150.
75. [75] Wintrobe MM, Lee GR, Boggs DR, Bithel TC, Athens JW, Foerester J, Clinical Hematology, Fifth ed., Philadelphia, PA, Lea and Febiger, 1961, p. 326.
76. [76] Becton-Dickinson. Unopette WBC/platelet determination for manual methods. Rutherford NJ: Becton, Dickinson, and Company; 1996.