Chemopreventive Potential of Chlorophyllin: A Review of the Mechanisms of Action and Molecular Targets

REFERENCES

• Riboli E: The role of metabolic carcinogenesis in cancer causation and prevention: evidence from the European Prospective Investigation into Cancer and Nutrition. Cancer Treat Res 159, 3–20, 2014.
   PubMedGoogle Scholar
• González-Vallinas M, González-Castejón M, Rodríguez-Casado A, and Ramírez de Molina A: Dietary phytochemicals in cancer prevention and therapy: a complementary approach with promising perspectives. Nutr Rev 71, 585–599, 2013.
   PubMed Web of Science ®Google Scholar
• PDR for Nutritional Supplements: In Chlorophyll/Chlorophyllin, Hendler SS and Rorvick,D (ed.). Montvale, NJ: Medical Economics Company, 2001, pp. 88–90.
   Google Scholar
• Tumolo T and Lanfer-Marquez U: Copper chlorophyllin: a food colorant with bioactive properties? Food Res Int 46, 451–459, 2012.
   Web of Science ®Google Scholar
• Ferguson LR, Philpott M, and Karunasinghe N: Dietary cancer and prevention using antimutagens. Toxicology 198, 147–159, 2004.
   PubMed Web of Science ®Google Scholar
• Williams DE: The rainbow trout liver cancer model: response to environmental chemicals and studies on promotion and chemoprevention. Comp Biochem Physiol C Toxicol Pharmacol 155, 121–127, 2012.
   PubMed Web of Science ®Google Scholar
• Wogan GN, Kensler TW, and Groopman JD: Present and future directions of translational research on aflatoxin and hepatocellular carcinoma. A review. Food Addit. Contam. Part A Chem. Anal. Control Expo Risk Assess 29, 249–257, 2012.
   PubMed Web of Science ®Google Scholar
• Fahey JW, Stephenson, KK, Dinkova-Kostova AT, Egner PA, Kensler TW, et al.: Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2 cytoprotective genes. Carcinogenesis 26, 1247–1255, 2005.
   PubMed Web of Science ®Google Scholar
• Linnewiel, K, Ernst H, Caris-Veyrat C, Ben-Dor A, Kampf A, et al.: Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system. Free Radic Biol Med 47, 659–667, 2009.
   PubMed Web of Science ®Google Scholar
• Dashwood RH, Breinholt V, and Bailey: Chemopreventive properties of chlorophyllin: inhibition of aflatoxin B1 (AFB1)-DNA binding in vivo and anti-mutagenic activity against AFB1 and two heterocyclic amines in the Salmonella mutagenicity assay. Carcinogenesis 12, 939–942, 1991.
   PubMed Web of Science ®Google Scholar
• Lagerqvist A, Hakansson D, Frank H, Seidel A, and Jenssen D: Structural requirements for mutation formation from polycyclic aromatic hydrocarbon dihydrodiol epoxides in their interaction with food chemopreventive compounds. Food Chem Toxicol 49, 879–886, 2011.
   PubMed Web of Science ®Google Scholar
• Grossi MR, Berni A, Pepe G, Mosesso P, Shivnani AA, et al.: A comparative study of the anticlastogeneic effects of chlorophyllin on N-methyl-N-nitro-N-nitrosoguanidine (MNNG) or 7,12-dimethylbenz(α) anthracene (DMBA) induced micronuclei in mammalian cells in vitro and in vivo. Toxicol Lett 214, 235–242, 2012.
   PubMed Web of Science ®Google Scholar
• Olvera O, Arceo C, and Zimmering S: Chlorophyllin [CHLN] and the mutagenicity of monofunctional alkylating agents in Drosophila: the action of CHLN need not include an influence on metabolic activation. Mutat Res 467, 113–117, 2000.
   PubMed Web of Science ®Google Scholar
• Pimentel E, Cruces MP, and Zimmering S: A further study of the role of copper in regard to the antimutagenic action of sodium copper chlorophyllin (SCC) in somatic cells of Drosophila melanogaster. Biomark Insights 8, 29–33, 2013.
   PubMedGoogle Scholar
• John K, Divi RL, Keshava C, Orozco CC, Schockley ME, et al.: CYP1A1 and CYP1B1 gene expression and DNA adduct formation in normal human mammary epithelial cells exposed to benzo[a]pyrene in the absence or presence of chlorophyllin. Cancer Lett 292, 254–260, 2010.
   PubMed Web of Science ®Google Scholar
• Ghosh AK, Sen S, Palit S, Ghosh A, Sharma A, et al.. Comparative efficacy of chlorophyllin in reducing cytotoxicity of some heavy metals. Biol Met 4, 158–161, 1991.
   PubMed Web of Science ®Google Scholar
• Negraes PD, Jordao BQ, Vicentini VE, and Mantovani MS: Anticlastogenicity of chlorophyllin in the different cell cycle phases in cultured mammalian cells. Mutat Res 557, 177–182, 2004;.
   PubMed Web of Science ®Google Scholar
• Diaz-Barriga Arceo S, Hernandez-Ceruelos A, Madrigal-Bujaidar E, and : Inhibitory effect of chlorophyllin on the frequency of micronuclei induced by sodium nitrite in mice. Phytother Res 16, 754–757, 2002.
   PubMed Web of Science ®Google Scholar
• Gradecka-Meesters D, Palus J, Prochazka G, Segerbäck D, et al.: Assessment of the protective effects of selected dietary anticarcinogens against DNA damage and cytogenetic effects induced by benzo[a]pyrene in C57BL/6J mice. Food Chem Toxicol 49, 1674–1683, 2011.
   PubMed Web of Science ®Google Scholar
• Yunos NM, Beale P, Yu JQ, and Huq F: Synergism from the combination of oxaliplatin with selected phytochemicals in human ovarian cancer cell lines. Anticancer Res 31, 4283–4289, 2011.
   PubMed Web of Science ®Google Scholar
• Pietrzak M, Halicka HD, Wieczorek Z, Wieczorek J, and Darzynkiewicz Z: Attenuation of acridine mutagen ICR-191-DNA interactions and DNA damage by the mutagen interceptor chlorophyllin. Biophys Chem 135, 69–75, 2008.
   PubMed Web of Science ®Google Scholar
• Chiu LC, Kong CK, and Ooi VE: The chlorophyllin-induced cell cycle arrest and apoptosis in human breast cancer MCF-7 cells is associated with ERK deactivation and cyclin D1 depletion. Int J Mol Med 16, 735–740, 2005.
   PubMed Web of Science ®Google Scholar
• Chimploy K, Diaz GD, Li Q, Carter O, Dashwood WM, Mathews CK, Williams DE, Bailey GS, Dashwood RH. E2F4 and ribonucleotide reductase mediate S-phase arrest in colon cancer cells treated with chlorophyllin. Int J Cancer 125, 2086–2094, 2009.
   PubMed Web of Science ®Google Scholar
• Ji WD, Jiang YG, Wang M, and Feng SM: Antitransforming activity of chlorophyllin against trans-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide. Zhonghua Yu Fang Yi Xue Za Zhi 37, 335–337, 2003.
   PubMedGoogle Scholar
• Fu J, Jiang YG, Bin XN, and Chen XM: Study on E-cadherin, cyclin D1 and cyclin E expression in anti-malignant transformation by chlorophyllin. Wei Sheng Yan Jiu 35, 678–681, 2006.
   PubMedGoogle Scholar
• Diaz GD, Li Q, and Dashwood RH: Caspase-8 and apoptosis-inducing factor mediate a cytochrome c-independent pathway of apoptosis in human colon cancer cells induced by the dietary phytochemical chlorophyllin. Cancer Res 63, 1254–1261, 2003.
   PubMed Web of Science ®Google Scholar
• Li B, Wu Z, Li W, Jia G, Lu J, et al.: Chlorophyllin e4 is a novel photosensitizer against human bladder cancer cells. Oncol Rep 27, 1455–1460, 2012.
   PubMed Web of Science ®Google Scholar
• Du L, Jiang N, Wang G, Chu Y, Lin W, et al.: Autophagy inhibition sensitizes bladder cancer cells to the photodynamic effects of the novel photosensitizer chlorophyllin e4. J Photochem Photobiol B 27, 1–10, 2014.
   Web of Science ®Google Scholar
• Koníčková R, Vaňková K, Vaníková J, Váňová K, Muchová L, et al.: Anti-cancer effects of blue-green alga Spirulina platensis, a natural source of bilirubin-like tetrapyrrolic compounds. Ann Hepatol 13, 273–283, 2014.
   PubMed Web of Science ®Google Scholar
• McQuistan TJ, Simonich MT, Pratt MM, Pereira CB, Hendricks JD, et al.: Cancer chemoprevention by dietary chlorophylls: a 12,000-animal dose-dose matrix biomarker and tumor study. Food Chem Toxicol 50, 341–352, 2012.
   PubMed Web of Science ®Google Scholar
• Williams DE: The rainbow trout liver cancer model: response to environmental chemicals and studies on promotion and chemoprevention. Comp Biochem Physiol C Toxicol Pharmacol 155, 121–127, 2012.
   PubMed Web of Science ®Google Scholar
• Simonich MT, Egner PA, Roebuck BD, Orner GA, Jubert C, et al.: Natural chlorophyll inhibits aflatoxin B1-induced multi-organ carcinogenesis in the rat. Carcinogenesis 28, 1294–1302, 2007.
   PubMed Web of Science ®Google Scholar
• Simonich MT, McQuistan T, Jubert C, Pereira C, Hendricks JD, et al.: Low-dose dietary chlorophyll inhibits multi-organ carcinogenesis in the rainbow trout. Food Chem Toxicol 46, 1014–1024, 2008.
   PubMed Web of Science ®Google Scholar
• Guo D, Horio DT, Grove JS, and Dashwood RH: Inhibition by chlorophyllin of 2-amino-3-methylimidazo-[4,5-f]quinoline-induced tumorigenesis in the male F344 rat. Cancer Lett 95, 161–165, 1995.
   PubMed Web of Science ®Google Scholar
• Pratt MM, Reddy AP, Hendricks JD, Pereira C, Kensler TW, et al.: The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers and final tumor outcome. Carcinogenesis 28, 611–624, 2007.
   PubMed Web of Science ®Google Scholar
• Hasegawa R, Hirose M, Kato T, Hagiwara A, Boonyaphiphat P, et al.: Inhibitory effect of chlorophyllin on PhIP-induced mammary carcinogenesis in female F344 rats. Carcinogenesis 16, 2243–2246, 1995.
   PubMed Web of Science ®Google Scholar
• Singh A, Singh SP, and Bamezai R: Modulatory influence of chlorophyllin on the mouse skin papillomagenesis and xenobiotic detoxication system. Carcinogenesis 17, 1459–1463, 1996.
   PubMed Web of Science ®Google Scholar
• Thiyagarajan P, Senthil Murugan R, Kavitha K, Anitha P, Prathiba D, et al.: Dietary chlorophyllin inhibits the canonical NF-κB signaling pathway and induces intrinsic apoptosis in a hamster model of oral oncogenesis. Food Chem Toxicol 50, 867–876, 2011.
   PubMed Web of Science ®Google Scholar
• Vidya Priyadarsini R, Kumar N, Khan I, Thiyagarajan P, Kondaiah P, et al.: Gene expression signature of DMBA-induced hamster buccal pouch carcinomas: Modulation by chlorophyllin and ellagic acid. PLoS One 7, e34628, 2012.
   PubMed Web of Science ®Google Scholar
• Castro DJ, Löhr CV, Fischer KA, Waters KM, Webb-Robertson BJ, et al.: Identifying efficacious approaches to chemoprevention with chlorophyllin, purified chlorophylls and freeze-dried spinach in a mouse model of transplacental carcinogenesis. Carcinogenesis 30, 315–320, 2009.
   PubMed Web of Science ®Google Scholar
• Thiyagarajan P, Kavitha K, Thautam A, Dixit M, and Nagini S: Dietary chlorophyllin abrogates TGFβ signaling to modulate the hallmark capabilities of cancer in an animal model of forestomach carcinogenesis. Tumour Biol 35, 6725–6737, 2014.
   PubMed Web of Science ®Google Scholar
• Wang R, Dashwood WM, Bailey GS, Williams DE, and Dashwood RH: Tumors from rats given 1,2-dimethylhydrazine plus chlorophyllin or indole-3-carbinol contain transcriptional changes in beta-catenin that are independent of beta-catenin mutation status. Mutat Res 601, 11–18, 2006.
   PubMed Web of Science ®Google Scholar
• Orner GA, Roebuck BD, Dashwood RH, and Bailey GS: Post-initiation chlorophyllin exposure does not modulate aflatoxin-induced foci in the liver and colon of rats. J Carcinog 5, 6, 2006.
   PubMedGoogle Scholar
• Blum CA, Xu M, Orner GA, Dario Diaz G, Li Q, et al.: Promotion versus suppression of rat colon carcinogenesis by chlorophyllin and chlorophyll: modulation of apoptosis, cell proliferation, and beta-catenin/Tcf signaling. Mutat Res 523–524, 217–223, 2003.
   PubMed Web of Science ®Google Scholar
• Egner PA, Wang JB, Zhu YR, Zhang BC, Wu Y, et al.: Chlorophyllin intervention reduces aflatoxin-DNA adducts in individuals at high risk for liver cancer. Proc Natl Acad Sci USA 98, 14601–14606, 2001.
   PubMed Web of Science ®Google Scholar
• Egner PA, Stansbury KH, Snyder EP, Rogers ME, Hintz PA, et al.: Identification and characterization of chlorin e(4) ethyl ester in sera of individuals participating in the chlorophyllin chemoprevention trial. Chem Res Toxicol 13, 900–906, 2000.
   PubMed Web of Science ®Google Scholar
• Jubert C, Mata J, Bench G, Dashwood RH, Pereira C, et al.: Effects of chlorophyll and chlorophyllin on low-dose aflatoxin B(1) pharmacokinetics in human volunteers. Cancer Prev Res (Phila) 2, 1015–1022, 2009.
   PubMed Web of Science ®Google Scholar
• Shaughnessy DT, Gangarosa LM, Schliebe, B, Umbach DM, Xu Z, et al:. Inhibition of fried meat-induced colorectal DNA damage and altered systemic genotoxicity in humans by crucifera, chlorophyllin, and yogurt. PLoS One 6, e18707, 2011.
   PubMed Web of Science ®Google Scholar
• John K, Keshava C, Richardson DL, Weston A, and Nath J: Transcriptional profiles of benzo(a)pyrene exposure in normal human mammary epithelial cells in the absence or presence of chlorophyllin. Mutat Res 640, 145–152, 2008.
   PubMed Web of Science ®Google Scholar
• Zhang J, Wang W, Yang F, Zhou X, Jin H, et al.: Comparative proteomic analysis of drug sodium iron chlorophyllin addition to Hep 3B cell line. Analyst 137, 4287–4294, 2012.
   PubMed Web of Science ®Google Scholar
• Oliveira PA, Colaco A, Chaves R, Guedes-Pinto H, De-La-Cruz PLF, et al.: Chemical carcinogenesis. An Acad Bras Cienc 79, 593–616, 2007.
   PubMed Web of Science ®Google Scholar
• Baird L and Dinkova-Kostova AT: The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85, 241–272, 2011.
   PubMed Web of Science ®Google Scholar
• Kavitha K, Thiyagarajan P, Rathna@Nandhini J, Mishra RK, and Nagini S: Chemopreventive effects of diverse dietary phytochemicals against DMBA-induced hamster buccal pouch carcinogenesis via the induction of Nrf2-mediated cytoprotective antioxidant, detoxification and DNA repair enzymes. Biochimie; 95, 1629–1639, 2013.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Guan L, Zhou PH, Mao LJ, Zhao ZM, et al.: The protective effect of chlorophyllin against oxidative damage and its mechanism. Zhonghua Nei Ke Za Zhi 51, 466–470, 2012.
   PubMedGoogle Scholar
• Zhang Y, Guan L, Wang X, Wen T, Xing J, et al.: Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2. Free Radic Res 42, 362–371, 2008.
   PubMed Web of Science ®Google Scholar
• Kamat JP, Boloor KK, and Devasagayam TP: Chlorophyllin as an effective antioxidant against membrane damage in vitro and ex vivo. Biochim Biophys Acta 1487, 113–127, 2000.
   PubMed Web of Science ®Google Scholar
• Kumar SS, Devasagayam TP, Bhusha B, and Verma NC: Scavenging of reactive oxygen species by chlorophyllin: an ESR study. Free Radic Res 35, 563–574, 2001.
   PubMed Web of Science ®Google Scholar
• Park KK, Park JH, Jung YJ, and Chung WY: Inhibitory effects of chlorophyllin, hemin and tetrakis (4-benzoic acid) porphyrin on oxidative DNA damage and mouse skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate as a possible anti-tumor promoting mechanism. Mutat Res 542,89–97, 2003.
   PubMed Web of Science ®Google Scholar
• Yu JW, Yang R, and Kim YS: Differential cytoprotective effect of copper- and iron-containing chlorophyllins against oxidative stress-mediated cell death. Free Radic Res 44, 655–667, 2010.
   PubMed Web of Science ®Google Scholar
• Boloor KK, Kamat JP, and Devasagayam TP: Chlorophyllin as a protector of mitochondrial membranes against gamma-radiation and photosensitization. Toxicology 155, 63–71, 2000.
   PubMed Web of Science ®Google Scholar
• Altieri DC: Survivin and IAP proteins in cell-death mechanisms. Biochem J 430, 199–205, 2010.
   PubMed Web of Science ®Google Scholar
• Ulukaya E, Acilan C, and Yilmaz Y: Apoptosis: why and how does it occur in biology? Cell Biochem Funct 29, 468–480, 2011.
   PubMed Web of Science ®Google Scholar
• Kumar M, Verma V, Nagpal R, Kumar A, Gautam SK, et al.: Effect of probiotic fermented milk and chlorophyllin on gene expressions and genotoxicity during AFB1-induced hepatocellular carcinoma. Gene 490, 54–59, 2011.
   Web of Science ®Google Scholar
• Bourboulia D and Stetler-Stevenson WG: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 20, 161–168, 2010.
   PubMed Web of Science ®Google Scholar
• Nagini S and Recking MMP: Relevance of Reversion-inducing cysteine-rich protein with Kazal motifs as a prognostic marker and therapeutic target for cancer (a review). Anticancer Agents Med Chem 12, 718–725, 2012.
   PubMed Web of Science ®Google Scholar
• Deryugina EI and Quigley JP: Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim Biophys Acta 1803, 103–120, 2010.
   PubMed Web of Science ®Google Scholar
• Nagini S, Priyadarsini RV, Veeravarmal V, and Mishra RK: Chlorophyllin abrogates canonical Wnt/β-catenin signaling pathway and angiogenesis to inhibit the development of DMBA-induced hamster cheek pouch carcinomas. Cell Oncol; 35, 385–395, 2012.
   Web of Science ®Google Scholar
• Yun CH, Son CG, Chung DK, and Han SH: Chlorophyllin attenuates IFN-gamma expression in lipopolysaccharide-stimulated murine splenic mononuclear cells via suppressing IL-12 production. Int Immunopharmacol 5, 1926–1935, 2005.
   PubMed Web of Science ®Google Scholar
• Perkins ND: The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer 12, 121–132, 2012.
   PubMed Web of Science ®Google Scholar
• Ding XW, Ding XL, Zheng S, and Yang HJ: CHL prevent colon neoplasms in mice and its selective inhibition on COX-2. Ai Zheng 23, 1409–1413, 2004.
   PubMedGoogle Scholar
• Cho KJ, Han SH, Kim BY, Hwang SG, Park KK, et al.: Chlorophyllin suppression of lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells. Toxicol Appl Pharmacol 166, 120–127, 2000.
   PubMed Web of Science ®Google Scholar
• Tian M, Neil JR, and Schiemann WP: Transforming growth factor-β and the hallmarks of cancer. Cell Signal 23, 951–962, 2011.
   PubMed Web of Science ®Google Scholar
• Kikuchi A, Yamamoto H, Sato A, and Matsumoto S: New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol 291, 21–71, 2011.
   PubMed Web of Science ®Google Scholar
• Carter D, Bailey GS, and Dashwood RH: The dietary phytochemical chlorophyllin alters E-cadherin and beta-catenin expression in human colon cancer cells. J Nutr 134, 3441S–3444S, 2004.
   PubMed Web of Science ®Google Scholar