Abstract
Although the therapeutic role of ajoene, an organosulfur compound of garlic, in cardiovascular diseases and mycology has been established, its usefulness in cancer treatment has only recently been suggested. We applied ajoene topically to the tumors of 21 patients with either nodular or superficial basal cell carcinoma (BCC). A reduction in tumor size was seen in 17 patients. Immunohistochemical assays for Bcl-2 expression in a selection of these tumors before and after treatment showed a significant decrease in this apoptosis-suppressing protein. On average, the percentage of tumor cells expressing the proliferation marker Ki-67 was not decreased, which suggests that the action of ajoene is not explained by a cytostatic effect. To obtain further insight into the mode of action of ajoene, the BCC cell line TE354T and a short-term primary culture of BCC were analyzed for apoptosis induction after treatment with the drug. Apoptosis was detected by morphology of the cells and by flow cytometry. Ajoene induced apoptosis in a dose- and time-dependent manner in these cultures. Taking together the results of the in vivo and in vitro studies, we conclude that ajoene can reduce BCC tumor size, mainly by inducing the mitochondria-dependent route of apoptosis.
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Ahmed N, Laverick L, Sammons J, Zhang H, Maslin DJ, Hassan HT (2001) Ajoene, a garlic-derived natural compound, enhances chemotherapy-induced apoptosis in human myeloid leukaemia CD34-positive resistant cells. Anticancer Res 21:3519–3523
Apitz-Castro R, Ledezma E, Escalante J, Jain MK (1986) The molecular basis of the antiplatelet action of ajoene: direct interaction with the fibrinogen receptor. Biochem Biophys Res Commun 141:145–150
Beutner KR, Geisse JK, Helman D, Fox TL, Ginkel A, Owens ML (1999) Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 41:1002–1007
Block E, Ahmad S, Catalfamo JL, Jain MK, Apitz-Castro R (1986) Antithrombotic organosulfur compounds from garlic: structural, mechanistic and synthetic studies. J Am Chem Soc 108:7045–7055
Broers JLV, Carney DN, Klein Rot M, Schaart G, Lane EB, Vooijs GP, Ramaekers FC (1986) Intermediate filament proteins in classic and variant types of small cell lung carcinoma cell lines: a biochemical and immunochemical analysis using a panel of monoclonal and polyclonal antibodies. J Cell Sci 83:37–60
Buiatti E, Palli D, Decarli A, Amadori D, Avellini C, Bianchi S, Biserni R, Cipriani F, Cocco P, Giacosa A, et al (1989) A case-control study of gastric cancer and diet in Italy. Int J Cancer 44:611–616
Dirsch VM, Gerbes AL, Vollmar AM (1998a) Ajoene, a compound of garlic, induces apoptosis in human promyeloleukemic cells, accompanied by generation of reactive oxygen species and activation of nuclear factor kappaB. Mol Pharmacol 53:402–407
Dirsch VM, Kiemer AK, Wagner H, Vollmar AM (1998b) Effect of allicin and ajoene, two compounds of garlic, on inducible nitric oxide synthase. Atherosclerosis 139:333–339
Dirsch VM, Antlsperger DS, Hentze H, Vollmar AM (2002) Ajoene, an experimental anti-leukemic drug: mechanism of cell death. Leukemia 16:74–83
Gravieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in-situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501
Hoffman EJ (1999) Cancer and the search for selective biochemical inhibitors. CRC Press, Boca Raton
Jacobs GH, Rippey JJ, Altini M (1982) Prediction of aggressive behaviour in basal cell carcinoma. Cancer 49:533–537
Kennedy JC, Pottier RH, Pross DC (1990) Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience. J Photochem Photobiol 6:143–148
Kilbourn RG, Belloni P (1990) Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin. J Natl Cancer Inst 82:772–776
Kooy AJW, Tank B, Vuzevski VD, Van Joost T (1995) Expression of cytokeratin 8 and other low molecular weight cytokeratins in human basal cell carcinoma. Anticancer Res 15:241–247
Krekels GAM, Verhaegh MEJM, Wagenaar S, Ramaekers FCS, Neumann HAM (1997) Keratins (K8 and K19) as potential markers of recurrent basal cell carcinoma. Eur J Dermatol 7:158–160
Kroncke KD, Fehsel K, Kolb-Bachofen V (1997) Nitric oxide: cytotoxicity versus cytoprotection—how, why, when, and where? Nitric Oxide 1:107–120
Ku NO, Gish R, Wright TL, Omary MB (2001) Keratin 8 mutations in patients with cryptogenic liver disease. N Engl J Med 344:1580–1587
Kwaspen FH, Smedts FM, Broos A, Bulten H, Debie WM, Ramaekers FC (1997) Reproducible and highly sensitive detection of the broad spectrum epithelial marker keratin 19 in routine cancer diagnosis. Histopathology 31:503–516
Kwon KB, Yoo SJ, Ryu DG, Yang JY, Rho HW, Kim JS, Park JW, Kim HR, Park BH (2002) Induction of apoptosis by diallyl disulfide through activation of caspase-3 in human leukemia HL-60 cells. Biochem Pharmacol 63:41–47
Lamas S, Michel T, Collins T, Brenner BM, Marsden PA (1992) Effects of interferon-gamma on nitric oxide synthase activity and endothelin-1 production by vascular endothelial cells. J Clin Invest 90:879–887
Leers MP, Kolgen W, Bjorklund V, Bergman T, Tribbick G, Persson B, Bjorklund P, Ramaekers FC, Bjorklund B, Nap M, Jornvall H, Schutte B (1999) Immunocytochemical detection and mapping of a cytokeratin 18 neo-epitope exposed during early apoptosis. J Pathol 187:567–572
Li M, Ciu J-R, Ye Y, Min J-M, Zhang L-H, Wang K, Gares M, Cros J, Wright M, Leung-Tack J (2002) Antitumor activity of Z-ajoene, a natural compound purified from garlic: antimitotic and microtubule-interaction properties. Carcinogenesis 23:573–579
Liew FY, Cox FE (1991) Nonspecific defence mechanism: the role of nitric oxide. Immunol Today 12:A17–21
Miller BH, Shavin JS, Cognetta A, Taylor RJ, Salasche S, Korey A, Orenberg EK (1997) Nonsurgical treatment of basal cell carcinomas with intralesional 5-fluorouracil/epinephrine injectable gel. J Am Acad Dermatol 36:72–77
Mooney EE, Ruis Peris JM, O'Neill A, Sweeney EC (1995) Apoptotic and mitotic indexes in malignant melanoma and basal cell carcinoma. J Clin Pathol 48:242–244
Nishikawa T, Yamada N, Hattori A, Fukuda H, Fujino T (2002) Inhibition of skin tumor promotion in mice. Biosci Biotechnol Biochem 66:2221–2223
Rowe DE, Carroll RJ, Day CL (1989) Long term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg 15:315–328
Slade HB (1998) Cytokine induction and modifying the immune response to human papilloma virus with imiquimod. Eur J Dermatol 8 [7 Suppl]:13–16
Smedts F, Ramaekers FCS, Robben H, Pruszczynski M, van Muijen G, Lane B, Leigh I, Vooijs P (1990) Changing patterns of keratin expression during progression of cervical intraepithelial neoplasia. Am J Pathol 136:657–668
Smedts F, Ramaekers F, Troyanovsky S, Pruszczynski M, Robben H, Lane B, Leigh I, Plantema F, Vooijs P (1992) Basal-cell keratins in cervical reserve cells and a comparison to their expression in cervical intraepithelial neoplasia. Am J Pathol 140:601–612
Staibano S, Lo Muzio L, Mezza E, Argenziano G, Tornillo L, Pannone G, De Rosa G (1999) Prognostic value of apoptotic index in cutaneous basal cell carcinomas of head and neck. Oral Oncol 35:541–547
Suschek CV, Krischel V, Bruch-Gerharz D, Berendji D, Krutmann J, Kroncke KD, Kolb-Bachofen V (1999) Nitric oxide fully protects against UVA-induced apoptosis in tight correlation with Bcl-2 up-regulation. J Biol Chem 274:6130–6137
Svanberg K, Andersson T, Killander D, Wang I, Stenram U, Andersson-Engels S, Berg R, Johansson J, Svanberg S (1994) Photodynamic therapy of non-melanoma malignant tumours of the skin using topical delta-amino levulinic acid sensitization and laser irradiation. Br J Dermatol 130:743–751
Telfer NR, Colver GB, Bowers PW (1999) Guidelines for the management of basal cell carcinomas. Br J Dermatol 141:415–423
Testerman TL, Gerster JF, Imbertson LM, Reiter MJ, Miller RL, Gibson SJ, Wagner TL, Tomai MA (1995) Cytokine induction by the immunomodulators imiquimod and S-27609. J Leukoc Biol 58:365–372
Thissen MRTM, Schroeter CA, Neumann HAM (2000) Effective photodynamic therapy with 5-aminolevulinic acid for nodular basal cell carcinomas using a preceding debulking technique. Br J Dermatol 142:338–339
Tilli CMLJ, Stavast-Kooy AJW, Ramaekers FCS, Neumann HAM (2002) Bax expression and growth behavior of basal cell carcinomas. J Cutan Pathol 29:79–87
van Engeland M, Nieland LJW, Ramaekers FCS, Schutte B, Reutelingsperger CPM (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31:1–9
Verhaegh MEJM, Sanders CJG, Arends JW, Neumann HAM (1995) Expression of the apoptosis-suppressing protein bcl-2 in non-melanoma skin cancer. Br J Dermatol 132:740–744
Wetzels RH, Kuijpers HJH, Lane EB, Leigh IM, Troyanovsky SM, Holland R, Van Haelst UJ, Ramaekers FC (1991) Basal cell-specific and hyperproliferation-related keratins in human breast cancer. Am J Pathol 138:751–763
Wikonkal NM, Berg RJW, van Haselen CW, Horkay I, Remenyik E, Begany A, Hunyadi J, van Vloten WA, de Gruijl FR (1997) Bcl-2 versus p53 protein expression and apoptotic rate in human nonmelanoma skin cancers. Arch Dermatol 133:599–602
Wolf P, Rieger E, Kerl H (1993) Topical photodynamic therapy with endogenous porphyrins after application of 5-aminolevulinic acid: an alternative treatment modality for solar keratosis, superficial squamous cell carcinomas and basal cell carcinomas? J Am Acad Dermatol 28:17–21
Yoshida S, Kasuga S, Hayashi N, Ushiroguchi T, Matsuura H, Nakagawa S (1987) Antifungal activity of ajoene derived from garlic. Appl Environ Microbiol 53:615–617
You WC, Blot WJ, Chang YS, Ershow A, Yang ZT, An Q, Henderson BE, Fraumeni JF Jr, Wang TG (1989) Allium vegetables and reduced risk of stomach cancer. J Natl Cancer Inst 81:162–164
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Tilli, C.M.L.J., Stavast-Kooy, A.J.W., Vuerstaek, J.D.D. et al. The garlic-derived organosulfur component ajoene decreases basal cell carcinoma tumor size by inducing apoptosis. Arch Dermatol Res 295, 117–123 (2003). https://doi.org/10.1007/s00403-003-0404-9
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DOI: https://doi.org/10.1007/s00403-003-0404-9