Cancer chemopreventive potential of volatile oil from black cumin seeds, Nigella sativa L., in a rat multi-organ carcinogenesis bioassay

Salim,Elsayed I.

doi:10.3892/ol_00000162

Cancer chemopreventive potential of volatile oil from black cumin seeds, Nigella sativa L., in a rat multi-organ carcinogenesis bioassay

Authors:
- Elsayed I. Salim
View Affiliations

Affiliations: Research Laboratory of Experimental and Molecular Carcinogenesis, Department of Zoology, Faculty of Science, Tanta University, Tanta 31527, Egypt. elsalem_777@yahoo.com
Published online on: September 1, 2010 https://doi.org/10.3892/ol_00000162
Pages: 913-924

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Nigella sativa (N. sativa) is a herbal plant of the Ranunculaceae family that has been widely used for various medicinal and nutritional purposes. Volatile oil extracts along with its major constituents, such as thymoquinone, have recently attracted considerable attention for their antioxidant, immunoprotective and antitumor properties. The present study was conducted to assess the chemopreventive potential of crude oils in N. sativa on tumor formation using a well-established rat multi-organ carcinogenesis model featuring initial treatment with five different carcinogens. Post-initiation administration of 1000 or 4000 ppm N. sativa volatile oil in the diet of male Wistar rats for 30 weeks significantly reduced malignant and benign colon tumor sizes, incidences and multiplicities. The treatment also significantly decreased the incidences and multiplicities of tumors in the lungs and in different parts of the alimentary canal, particularly the esophagus and forestomach. Bromodeoxyuridine labeling indices, reflecting cell proliferation were significantly decreased in various organs and lesions after treatment with the two doses of N. sativa. The plasma levels of insulin growth factor, triglycerides and prostaglandin E2 were also altered. The findings show, for the first time, that N. sativa administration exerts potent inhibitory effects on rat tumor development and on cellular proliferation in multiple organ sites. In particular, the ability to significantly inhibit murine colon, lung, esophageal and forestomach tumors was demonstrated in the post-initiation phase, with no evidence of clinical side effects. The mechanisms are likely to be related to suppression of cell proliferation.

View Figures

View References

1	Khan N and Sultana S: Inhibition of two stage renal carcinogenesis, oxidative damage and hyperproliferative response by Nigella sativa. Eur J Cancer Prev. 14:159–168. 2005. View Article : Google Scholar : PubMed/NCBI
2	Farah IO: Assessment of cellular responses to oxidative stress using MCF-7 breast cancer cells, black seed (N. Sativa L.) extracts and H₂O₂. Int J Environ Res Public Health. 2:411–419. 2005. View Article : Google Scholar : PubMed/NCBI
3	Hanafy M and Hatem M: Studies on the antimicrobial activity of Nigella sativa seed (black cumin). J Ethnopharmacol. 34:275–278. 1991. View Article : Google Scholar
4	Salomi N, Nair S, Jayawardhanan K, Varghese D and Panikkar K: Anti-tumor principles from Nigella sativa seeds. Cancer Lett. 63:41–46. 1992. View Article : Google Scholar
5	Landa P, Marsik P, Havlik J, Kloucek P, Vanek T and Kokoska L: Evolution of antimicrobial and anti-inflammatory activities of seed extracts from six Nigella species. J Med Food. 12:408–415. 2009. View Article : Google Scholar : PubMed/NCBI
6	Suboh SM, Bilto YY and Aburjai TA: Protective effects of selected medicinal plants against protein degradation, lipid peroxidation and deformability loss of oxidatively stressed human erythrocytes. Phytother Res. 18:280–284. 2004. View Article : Google Scholar
7	Salim EI and Fukushima S: Chemopreventive potential of volatile oil from black cumin (Nigella sativa L.) seeds against rat colon carcinogenesis. Nutr Cancer. 45:195–202. 2003. View Article : Google Scholar : PubMed/NCBI
8	Ito N, Shirai S and Fukushima S: Medium-term for carcinogens using multiorgan models. In: Modification of Tumor Development in Rodents. Progress in Experimental Tumor Research. Ito N and Sugano H: Karger; Basel: pp. 41–57. 1991
9	Ito N, Tsuda H, Tatematsu M, et al: Enhancing effect of various hepatocarcinogens on induction of preneoplastic glutathione S-transferase placental form positive foci in rats – an approach for a new medium-term bioassay system. Carcinogenesis. 9:387–394. 1988.PubMed/NCBI
10	Kurata Y, Hagiwara A, Tamano S, Shibata M, Tanaka H, Yamada M, Ito H and Fukushima S: Modifying effects of beraprost sodium (TRK-100) on N-methyl-N-nitrosourea (MNU) carcinogenesis in F344 rats. J Toxicol Sci. (Suppl 1): 1–39. 1989. View Article : Google Scholar : PubMed/NCBI
11	Konishi Y, Yamamoto K, Eimoto H, Tsutsumi M, Sugimura M, Nii H and Mori Y: Carcinogenic activity of endogenously synthesized N-nitrosobis(2-hydroxypropyl)amine in rats. IARC Sci Publ. 105:318–321. 1991.PubMed/NCBI
12	Bird RP: Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett. 37:147–151. 1987. View Article : Google Scholar : PubMed/NCBI
13	Salim EI, Wanibuchi H, Morimura K, Kim S, Yano Y, Yamamoto S and Fukushima S: Inhibitory effects of 1,3-diaminopropane, an ornithine decarboxylase inhibitor, on rat two-stage urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine. Carcinogenesis. 21:195–203. 2000. View Article : Google Scholar
14	Spinardi-Barbisan AL, Kaneno R, Rodrigues MA, Fávero Salvadori DM, Trindade Moreira EL, Barbisan LF and Viana de Camargo JL: Lymphoproliferative response and T lymphocyte subsets in a medium-term multiorgan bioassay of carcinogenesis in Wistar rats. Cancer Lett. 154:121–129. 2000. View Article : Google Scholar : PubMed/NCBI
15	Doi K, Sakai K, Tanaka R, Toma K, Yamaguchi T, Wei M, Fukushima S and Wanibuchi H: Chemopreventive effects of 13alpha, 14alpha-epoxy-3beta-methoxyserratan-21beta-ol (PJJ-34), a serratane-type triterpenoid, in a rat multi-organ carcinogenesis bioassay. Cancer Lett. 289:161–169. 2009. View Article : Google Scholar : PubMed/NCBI
16	Hagiwara A, Tanaka H, Imaida K, Tamano S, Fukushima S and Ito N: Correlation between medium-term multi-organ carcinogenesis bioassay data and long-term observation results in rats. Jpn J Cancer Res. 84:237–245. 1993. View Article : Google Scholar : PubMed/NCBI
17	Mabrouk GM, Moselhy SS, Zohny SF, Ali EM, Helal TE, Amin AA and Khalifa AA: Inhibition of methylnitrosourea (MNU) induced oxidative stress and carcinogenesis by orally administered bee honey and Nigella grains in Sprague Dawely rats. J Exp Clin Cancer Res. 21:341–346. 2002.PubMed/NCBI
18	Badary OA and Gamal El-Din AM: Inhibitory effects of thymoquinone against 20-methylcholanthrene-induced fibrosarcoma tumorigenesis. Cancer Detect Prev. 25:362–368. 2001.PubMed/NCBI
19	Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammed M, Padhye S, Sarkar FH and Mohammed RM: Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 69:5575–5583. 2009. View Article : Google Scholar : PubMed/NCBI
20	Babayan VK, Koottungal D and Halaby GA: Proximate analysis, fatty acid, and amino acid composition of Nigella sativa L. seeds. J Food Sci. 43:1314–1319. 1978. View Article : Google Scholar
21	Ali BH and Blunden G: Pharmacological and toxicological properties of Nigella sativa. Phytother Res. 17:299–305. 2003. View Article : Google Scholar
22	Ghosheh OA, Houdi AA and Crooks PA: High performance liquid chromatographic analysis of the pharmacologically active quinines and related compounds in the oil of the black seed (Nigella sativa L.). J Pharm Biomed Anal. 19:757–762. 1999. View Article : Google Scholar : PubMed/NCBI
23	Morikawa T, Xu F, Ninomiya K, Matsuda H and Yoshikawa M: Nigellamines A3, A4, A5, and C, new dolabellane-type diterpene alkaloids, with lipid metabolism-promoting activities from the Egyptian medicinal food black cumin. Chem Pharm Bull. 52:494–497. 2004. View Article : Google Scholar : PubMed/NCBI
24	Liu YM, Yang JS and Liu QH: A new alkaloid and its artificial derivative with an indazole ring from Nigella glandulifera. Chem Pharm Bull. 52:454–455. 2004. View Article : Google Scholar : PubMed/NCBI
25	Islam SN, Begum P, Ahsan T, Huque S and Ahsan M: Immunosuppressive and cytotoxic properties of Nigella sativa. Phytother Res. 18:395–398. 2004. View Article : Google Scholar : PubMed/NCBI
26	Le PM, Benhaddou-Andaloussi A, Elimadi A, Settaf A, Cherrah Y and Haddad PS: The petroleum ether extract of Nigella sativa exerts lipid-lowering and insulin-sensitizing actions in the rat. J Ethnopharmacol. 94:251–259. 2004.PubMed/NCBI
27	Kocyigit Y, Atamer Y and Uysal E: The effect of dietary supplementation of Nigella sativa L. on serum lipid profile in rats. Saudi Med J. 30:893–896. 2009.PubMed/NCBI
28	Yi T, Cho SG, Yi Z, Pang X, Rodriguez M, Wang Y, Sethi G, Aggarwal BB and Liu M: Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signalling pathways. Mol Cancer Ther. 7:1789–1796. 2008. View Article : Google Scholar : PubMed/NCBI
29	Chakraborty T, Chatterjee A, Rana A, Srivastawa S, Damodaran S and Chatterjee M: Cell proliferation and hepatocarcinogenesis in rat initiated by diethylnitrosamine and promoted by phenobarbital: potential roles of early DNA damage and liver metallothionein expression. Life Sci. 81:489–499. 2007. View Article : Google Scholar
30	Gratzner HG: Monoclonal antibody to 5-bromo-2 and 5-iododeoxyuridine: a new reagent for detection of DNA replication. Science. 218:474–475. 1982. View Article : Google Scholar : PubMed/NCBI
31	McGinley JN, Knott KK and Thompson HJ: Effect of fixation and epitope retrieval on BrdU indices in mammary carcinomas. J Histochem Cytochem. 48:355–362. 2000. View Article : Google Scholar : PubMed/NCBI
32	Rosenfeld RG, Wilson DM, Lee PD and Hintz RL: Insulin-like growth factors I and II in evaluation of growth retardation. J Pediatr. 109:428–433. 1986. View Article : Google Scholar : PubMed/NCBI
33	Bucolo G and David H: Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem. 19:476–482. 1973.PubMed/NCBI
34	Allain CC, Poon LS, Chan CS, Richmond W and Fu PC: Enzymatic determination of total serum cholesterol. Clin Chem. 20:470–475. 1974.PubMed/NCBI
35	Wasan KM, Holtorf L, Subramanian R, Cassidy SM, Pritchard PH, Stewart DJ, Novak E and Moghadasian MH: Assessing plasma pharmacokinetics of cholesterol following oral co-administration with a novel vegetable stanol mixture to fasting rats. J Pharm Sci. 90:23–28. 2001. View Article : Google Scholar : PubMed/NCBI
36	Boorman GA, Eustis SL, Elwell MR, Montgomry CA and MacKenzie WF: Pathology of the Fischer Rat Reference & Atlas. Academic Press; San Diego: 1990
37	Hsu SM, Raine L and Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 29:577–580. 1981. View Article : Google Scholar : PubMed/NCBI
38	El-Aziz MA, Hassan HA, Mohamed MH, Meki AR, Abdel-Ghaffar SK and Hussein MR: The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model. Int J Exp Pathol. 86:383–396. 2005.PubMed/NCBI
39	Salomi MJ, Nair SC and Pannikar KR: Inhibitory effects of Nigella sativa and Saffron (Crocus sativus) on chemical carcinogenesis in mice. Nutr Cancer. 16:67–72. 1991.
40	El-Mofty MM, Abdel-Galil AM, Shwaireb MH, et al: Prevention of skin tumors induced by 7,12-dimethylbenz(a)anthracene in mice by black seed oil. Oncol Rep. 4:139–141. 1997.PubMed/NCBI
41	Al-Johar D, Shinwari N, Arif J, Al-Sanea N, Jabbar AA, El-Sayed R, Mashhour A, Billedo G, El-Doush I and Al-Saleh I: Role of Nigella sativa and a number of its antioxidant constituents towards azoxymethane-induced genotoxic effects and colon cancer in rats. Phytother Res. 22:1311–1323. 2008.
42	Rooney S and Ryan MF: Effects of alpha-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer Res. 25:2199–2204. 2005.PubMed/NCBI
43	Gali-Muhtasib H, Diab-Assaf M, Boltze C, Al-Hmaira J, Hartig R, Roessner A and Schneider-Stock R: Thymoquinone extracted from black seed triggers apoptotic cell death in human colorectal cancer cells via a p53-dependent mechanism. Int J Oncol. 25:857–866. 2004.PubMed/NCBI
44	Norwood AA, Tan M, May M, Tucci M and Benghuzzi H: Comparison of potential chemotherapeutic agents, 5-fluoruracil, green tea, and thymoquinone, on colon cancer cells. Biomed Sci Instrum. 42:350–356. 2006.PubMed/NCBI
45	Kumara SS and Huat BT: Extraction, isolation and characterisation of antitumor principle, alpha-hederin, from the seeds of Nigella sativa. Planta Med. 67:29–32. 2001. View Article : Google Scholar : PubMed/NCBI
46	Farah N, Benghuzzi H, Tucci M and Cason Z: The effects of isolated antioxidants from black seed on the cellular metabolism of A549 cells. Biomed Sci Instrum. 41:211–216. 2005.PubMed/NCBI
47	Abbas AT, Abdel-Aziz MM, Zalata KR and el-D Abd Al-Galel T: Effect of dexamethasone and Nigella sativa on peripheral blood eosinophil count, IgG1 and IgG2a, cytokine profiles and lung inflammation in a murine model of allergic asthma. Egyp J Immunol. 12:95–102. 2005.
48	El Mezayen R, El Gazzar M, Nicolls MR, Marecki JC, Dreskin SC and Nomiyama H: Effect of thymoquinone on cyclooxygenase expression and prostaglandin production in a mouse model of allergic airway inflammation. Immunol Lett. 106:72–81. 2006.PubMed/NCBI
49	Hossein BM, Nasim V and Sediqa A: The protective effect of Nigella sativa on lung injury of sulfur mustard-exposed Guinea pigs. Exp Lung Res. 34:183–194. 2008.
50	Keyhanmanesh R, Boskabady MH, Eslamizadeh MJ, Khamneh S and Ebrahimi MA: The effect of thymoquinone, the main constituent of Nigella sativa, on tracheal responsiveness and white blood cell count in lung lavage of sensitized Guinea pigs. Planta Med. 76:2187–222. 2009.
51	Kanter M: Effects of Nigella sativa seed extract on ameliorating lung tissue damage in rats after experimental pulmonary aspirations. Acta Histochem. 111:393–403. 2009.
52	El Gazzar M, El Mezayen R, Nicolls MR, Marecki JC and Dreskin SC: Downregulation of leukotriene biosynthesis by thymoquinone attenuates airway inflammation in a mouse model of allergic asthma. Biochim Biophys Acta. 1760:1088–1095. 2006.PubMed/NCBI
53	Boskabady MH and Farhadi J: The possible prophylactic effect of Nigella sativa seed aqueous extract on respiratory symptoms and pulmonary function tests on chemical war victims: a randomized, double-blind, placebo-controlled trial. J Altern Complement Med. 14:1137–1144. 2008.
54	Badary OA, Al-Shabanah OA, Nagi MN, Al-Rikabi AC and Elmazar MM: Inhibition of benzo(a)pyrene-induced forestomach carcinogenesis in mice by thymoquinone. Eur J Cancer Prev. 8:435–440. 1999. View Article : Google Scholar : PubMed/NCBI
55	Al Mofleh IA, Alhaider AA, Mossa JS, Al-Sohaibani MO, Al-Yahya MA, Rafatullah S and Shaik SA: Gastroprotective effect of an aqueous suspension of black cumin Nigella sativa on necrotizing agent-induced gastric injury in experimental animals. Saudi J Gastroenterol. 14:128–134. 2008.PubMed/NCBI
56	Kanter M, Demir H, Karakaya C and Ozbek H: Gastroprotective activity of Nigella sativa L oil and its constituent, thymoquinone, against acute alcohol-induced gastric mucosal injury in rats. World J Gastroenterol. 11:6662–6666. 2005.
57	Kanter M, Coskun O and Uysal H: The antioxidative and antihistaminic effect of Nigella sativa and its major constituent, thymoquinone, on ethanol-induced gastric mucosal damage. Arch Toxicol. 80:217–224. 2006.PubMed/NCBI
58	El-Abhar HS, Abdallah DM and Saleh S: Gastroprotective activity of Nigella sativa oil and its constituent, thymoquinone, against gastric mucosal injury induced by ischaemia/reperfusion in rats. J Ethnopharmacol. 84:251–258. 2003.
59	Morimura S, Susuki T, Hochi S, Yuki A, Nomura K and Kitagawa T: Transactivation of GST-P gene during hepatocarcinogenesis of rat. Proc Natl Acad Sci USA. 90:2065–2068. 1993. View Article : Google Scholar : PubMed/NCBI
60	Ogiso T, Tatematsu M, Tamano S, Tsuda H and Ito N: Comparison of dose dependent effects of chemical carcinogens on induction of glutathione S-transferase placental form positive foci in a short term assay and of hepatocellular carcinomas in a long-term assay. Toxicol Pathol. 13:257–265. 1985. View Article : Google Scholar : PubMed/NCBI
61	Ogiso T, Tatematsu M, Tamano S, Hasegawa R and Ito N: Correlation between medium-term bioassay system data and results of long-term testing of rats. Carcinogenesis. 11:561–566. 1990. View Article : Google Scholar : PubMed/NCBI
62	Iddamaldeniya SS, Thabrew MI, Wickramasinghe SM, Ratnatunge N and Thammitiyagodage MG: A long-term investigation of the anti-hepatocarcinogenic potential of an indigenous medicine comprised of Nigella sativa, Hemidesmus indicus and Smilax glabra. J Carcinog. 9:5–11. 2006.PubMed/NCBI
63	Nagi MN and Almakki HA: Thymoquinone supplementation induces quinone reductase and glutathione transferase in mice liver: possible role in protection against chemical carcinogenesis and toxicity. Phytother Res. 23:1295–1298. 2009. View Article : Google Scholar
64	Ibrahim ZS, Ishizuka M, Soliman M, ElBohi K, Sobhy W, Muzandu K, Elkattawy AM, Sakamoto KQ and Fujita S: Protection by Nigella sativa against carbon tetrachloride-induced downregulation of hepatic cytochrome P450 isozymes in rats. Jpn J Vet Res. 56:119–128. 2008.
65	Ait Mbarek L, Ait Mouse H, Elabbadi N, Bensalah M, Gamouh A, Aboufatima R, Benharref A, Chait A, Kamal M, Dalal A and Zyad A: Anti-tumor properties of black seed (Nigella sativa L.) extracts. Braz J Med Biol Res. 40:839–847. 2007.PubMed/NCBI
66	Cemek M, Enginar H, Karaca T and Unak P: In vivo radioprotective effects of Nigella sativa L oil and reduced glutathione against irradiation-induced oxidative injury and number of peripheral blood lymphocytes in rats. Photochem Photobiol. 82:1691–1696. 2006.
67	Nergiz C and Otles S: Chemical composition of Nigella sativa L. seeds. Food Chem. 48:259–261. 1993. View Article : Google Scholar
68	Bartsch H, Nair J and Owen RW: Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers. Carcinogenesis. 20:2209–2218. 1999. View Article : Google Scholar : PubMed/NCBI
69	Badary OA, Taha RA, Gamal El-Din AM and Abdel-Wahab MH: Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol. 26:87–98. 2003. View Article : Google Scholar
70	Ramadan MF, Kroh LW and Mörsel JT: Radical scavenging activity of black cumin (Nigella sativa L.), coriander (Coriandrum sativum L.), and niger (Guizotia abyssinica Cass.) crude seed oils and oil fractions. J Agric Food Chem. 51:6961–6969. 2003.PubMed/NCBI
71	Wattenberg LW: Chemoprevention of cancer by naturally occur-ring and synthetic compounds. Cancer Chemoprevention. Wattenberg L, Lipkin M, Boone CW and Keloff GJ: CRC Press; Boca Raton: pp. 19–39. 1992
72	Mukhtar H, Das M and Bickers DR: Inhibition of 3-methyl-cholanthrene-induced skin tumorigenesis in BALB/c mice by oral feeding of trace amounts of ellagic acid in drinking water. Cancer Res. 46:2262–2265. 1986.PubMed/NCBI
73	Ames BN, Gold LS and Willet WC: The causes and prevention of cancer. Proc Natl Acad Sci USA. 92:5258–5265. 1995. View Article : Google Scholar : PubMed/NCBI
74	Grossmann ME, Mizuno NK, Dammen ML, Schuster T, Ray A and Cleary MP: Eleostearic acid inhibits breast cancer proliferation by means of an oxidation-dependent mechanism. Cancer Prev Res. 2:879–886. 2009. View Article : Google Scholar : PubMed/NCBI
75	Prabhu PN, Ashokkumar P and Sudhandiran G: Antioxidative and antiproliferative effects of astaxanthin during the initiation stages of 1,2-dimethyl hydrazine-induced experimental colon carcinogenesis. Fundam Clin Pharmacol. 23:225–234. 2009. View Article : Google Scholar
76	Beales IL and Ogunwobi OO: Microsomal prostaglandin E synthase-1 inhibition blocks proliferation and enhances apoptosis in oesophageal adenocarcinoma cells without affecting endothelial prostacyclin production. Int J Cancer. 126:2247–2255. 2010.
77	Abu-Bedair FA, El-Gamal BA, Ibrahim NA and El-Aaser AA: Serum lipids and tissue DNA content in Egyptian female breast cancer patients. Jpn J Clin Oncol. 33:278–282. 2003. View Article : Google Scholar : PubMed/NCBI
78	Menendez JA: Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives. Biochim Biophys Acta. 1801:381–391. 2010. View Article : Google Scholar