Abnormal regulation of apoptosis is an important aspect of tumour development. Capsaicin, an extract of red chilli pe ppers, has been shown to inhibit growth of melanoma and other malignant cell lines and HA14-1 is an organic com pound that directly induces apoptosis by binding to Bcl-2 protein. The aim of this work was to investigate whether com bination therapy with capsaicin and HA14-1 might hold any promise for the treatment of melanoma. Three melanoma cell lines of a range of aggressive potential, melanocytes and fibroblasts were examined, looking at the effects of both drugs singly and in combination on cell viability and induction of apoptosis. This comparative study showed that mela noma cells and melanocytes have a similar sensitivity to capsaicin while fibroblasts are more resistant to it. HA14-1 , as expected , induced apoptosis in all cells at relatively low concentrations. A combination of the two agents produced the expected results of an additive effect for 2 (HBL and A375SM) out of 3 melanoma cell lines in inducing apoptosis, but encouragingly for the most metastatically aggressive cancer cell line (C8161), a combination of the two showed a syn ergistic induction of apoptosis.
F. Balkwill and A. Mantovani, “Inflammation and Cancer: Back to Virchow?” Lancet, Vol. 357, No. 9255, 2001, pp 539-545. doi:10.1016/S0140-6736(00)04046-0
L. M. Coussens and Z. Werb, “Inflammation and Cancer,” Nature, Vol. 240, No. 6917, 2002, pp. 860-867. doi:10.1038/nature01322
M. Karin, “Cancer Research in Flames,” The Scientist, Vol. 19, No. 23, 2005, pp. 24-25.
J. Marx, “Inflammation and Cancer: The Link Grows Stronger,” Science, Vol. 306, No. 5698, 2004, pp. 966-968. doi:10.1126/science.306.5698.966
A. Mantovani, “Inflammation by Remote Control,” Nature, Vol. 435, No. 704, 2005, pp. 752-753. doi:10.1038/435752a
F. Balkwill, “Cancer and the Chemokine Network,” Nature, Vol. 4, No. 7, 2004, pp. 540-550.
E. Shacter and S. A. Weitzman, “Chronic Inflammation and Cancer,” Oncology, Vol. 16, No. 2, 2002, pp. 217-232.
R. E. Harris, J. Beebe-Donk, H. Doss and D. B. Doss, “Aspirin, Ibuprofen, and Other Non-Steroidal Anti-Inflammatory Drugs in Cancer Prevention: A Critical Review of Non-Selective COX-2 Blockade,” Oncology Reports, Vol. 13, No. 4, 2005, pp. 559-583.
P. Dasgupta, V. Chandiramani, M. C. Parkinson, A. Beckett and C. J. Fowler, “Treating the Human Bladder with Capsaicin: Is It Safe?” European Urology, Vol. 33, No. 1, 1998, pp. 28-31. doi:10.1159/000019531
D. J. Morré, E. Sun, C. Geilen, L. Y. Wu, R. de Cabo, K. Krasagakis, C. E. Orfanos and D. M. Morre, “Capsaicin Inhibits Plasma Membrane NADH Oxidase and Growth of Human and Mouse Melanoma Lines,” European Journal of Cancer, Vol. 32, No. 11, 1996, pp. 1995-2003. doi:10.1016/0959-8049(96)00234-1
S. S. Brar, T. P. Kennedy, A. R. Whorton, A. B. Sturrock, T. P. Huecksteadt, A. J. Ghio and J. R. Hoidal, “Reactive Oxygen Species from NAD(P)H:Quinone Oxidoreductase Constitutively Activate NF-kappaB in Malignant Melanoma Cells,” Cell Physiology: American Journal of Physiology, Vol. 280, No. 3, 2001, pp. 659-676.
V. A. Trinh, “Current Management of Metastatic Melanoma,” American Journal of Health-System Pharmacy, Vol. 65, No. 24, 2008, pp. S3-S8. doi:10.2146/ajhp080460
J. Poust, “Targeting Metastatic Melanoma,” American Journal of Health-System Pharmacy, Vol. 65, No. 24, 2008, pp. S9-S15. doi:10.2146/ajhp080461
S. S. Agarwala, U. Keilholz, E. Gilles, A. Y. Bedikian, J. Wu, R. Kay, C. A. Stein, L. M. Itri, S. Suciu and A. M. Eggermont, “LDH Correlations with Survival in Advanced Melanoma from Two Large, Randomised Trials (Oblimersen GM301 and EORTC 18951),” European Journal of Cancer, Vol. 45, No. 10, 2009, pp. 1807-1814. doi:10.1016/j.ejca.2009.04.016
F. S. Hodi, S. J. O’Day, D. F. McDermott, R. W. Weber, J. A. Sosman, J. B. Haanen, R. Gonzalez, C. Robert, D. Schadendorf, J. C. Hassel, W. Akerley, A. J. van den Eertwegh, J. Lutzky, P. Lorigan, J. M. Vaubel, G. P. Linette, D. Hogg, C. H. Ottensmeier, C. Lebbé, C. Peschel, I. Quirt, J. I. Clark, J. D. Wolchok, J. S. Weber, J. Tian, M. J. Yellin, G. M. Nichol, A. Hoos and W. J. Urba, “Improved Survival with Ipilimumab in Patients with Metastatic Melanoma,” The New England Journal of Medicine, Vol. 363, No. 8, 2010, pp. 711-723. doi:10.1056/NEJMoa1003466
J. A. Sosman, K. B. Kim, L. Schuchter, R. Gonzalez, A. C. Pavlick, J. S. Weber, G. A. McArthur, T. E. Hutson, S. J. Moschos, K. T. Flaherty, P. Hersey, R. Kefford, D. Lawrence, I. Puzanov, K. D. Lewis, R. K. Amaravadi, B. Chmielowski, H. J Lawrence, Y. Shyr, F. Ye, J. Li, K. B. Nolop, R. J. Lee, A. K. Joe and A. Ribas, “Survival in BRAF V-600-Mutant Advanced Melanoma Treated with Vemurafenib,” The New England Journal of Medicine, Vol. 366, No. 8, 2012, pp. 707-714. doi:10.1056/NEJMoa1112302
D. Tian, S. G. Das, J. M Doshi, J. Peng, J. Lin and C. Xing, “sHA14-1, a Stable and ROS-Free Antagonist against Anti-Apoptotic Bcl-2 Proteins, Bypasses Drug Resistances and Synergizes Cancer Therapies in Human Leukaemia Cell,” Cancer Letters, Vol. 259, No. 2, 2007, pp. 198-208. doi:10.1016/j.canlet.2007.10.012
J. L. Wang, D. Liu, Z. L. Zhang, S. Shan, X. Han, S. M. Srinicasula, C. M. Croce, E. S. Alnemri and Z. Huang, “Structure-Based Discovery of an Organic Compound that Binds Bcl-2 Protein and Induces Apoptosis of Tumor Cells,” Proceeding of National Acadamiy Sciences of the United State of America, Vol. 97, No. 13, 2000, pp. 712-719. doi:10.1073/pnas.97.13.7124
U. Zangemeister-Wittke and A. Ziegler, “Bcl-2 Antisense Therapy for Cancer: The Art of Persuading Tumour Cells to Commit Suicide,” Apoptosis, Vol. 3, No. 2, 1998, pp. 67-74. doi:10.1023/A:1009636722713
J. M. Kozlowski, I. R. Hart, I. J. Fidler and N. Hanna, “A Human Melanoma Line Heterogeneous with Respect to Metastatic Capacity in Athymic Nude Mice,” Journal of the National Cancer Institute, Vol. 72, No. 4, 1984, pp 913-917.
G. E. Ghanem, G. Comunale, A. Libert, A. VercammenGrandjean and F. J. Lejeune, “Evidence for Alpha-Melanocytes-Stimulating Hormone (Alpha-MSH) Receptors on Human Malignant Melanoma Cells,” International Journal of Cancer, Vol. 41, No. 2, 1988, pp. 248-255. doi:10.1002/ijc.2910410216
P. Eves, C. Layton, S. Hedley, R. Dawson, M. Wagner, R. Morandini, G. Ghanem and S. MacNeil, “Characterisation of an In Vitro Model of Human Melanoma Invasion Based on Reconstructed Human Skin,” British Journal of Dermatology, Vol. 142, No. 2, 2000, pp. 210-222. doi:10.1046/j.1365-2133.2000.03287.x
Y. G. Kim, M. J. Kim, J.-S. Lim, M.-S. Lee, J. S. Kim and Y. D. Yoo, “ICAM-3-Induced Cancer Cell Proliferation through the PI3K/Akt Pathway,” Cancer Letters, Vol. 239, No. 1, 2006, pp. 103-110. doi:10.1016/j.canlet.2005.07.023
E. Katerinaki, J. W. Haycock, R. Lalla, K. E. Carlson, Y. Yang, R. P. Hill, P. C. Lorigan and S. MacNeil, “Sodium Salicylate Inhibists TNF-Alpha-Induced NF-kappaB Activation, Cell Migration, Invasion and ICAM-1 Expression in Human Melanoma Cells,” Melanoma Research, Vol. 16, No. 1, 2006, pp. 11-22. doi:10.1097/01.cmr.0000195698.58013.53
B. B. Aggarwal, “Signalling Pathways of the TNF Superfamily: A Double Edged Sword,” Nature Reviews Immunology, Vol. 3, No. 9, 2003, pp. 745-756. doi:10.1038/nri1184
S. Aggarwal, Y. Takada, A. M. Mhashilkar, K. Sieger, S. Chada and B. B. Aggarwal, “Melanoma DifferentiationAssociated Gene7/IL-24 Gene Enhances NF-kB Activation and Suppresses Apoptosis Induced by TNF,” Journal of Immunology, Vol. 173, No. 7, 2004, pp. 4368-4376.
E. Pikarsky and Y. Ben-Neriah, “NF-kB Inhibition: A Double-Edged Sword in Cancer?” European Journal of Cancer, Vol. 42, No. 6, 2006, pp. 779-784. doi:10.1016/j.ejca.2006.01.011
W.-W. Lin and M. Karin, “A Cytokine-Mediated Link between Innate Immunity, Inflammation, and Cancer,” Journal of Clinical Investigation, Vol. 117, No. 5, 2007, pp. 1175-1183. doi:10.1172/JCI31537
J. P. Monk, G. Phillips, R. Waite, J. Kuhn, L. J. Schaaf, G. A. Otterson, D. Guttridge, C. Rhoades, M. Shah, T. Criswell, M. A. Caligiuri and M. A. Villalona-Calero, “Assessment of Tumor Necrosis Factor Alpha Blockade as an Intervention to Improve Tolerability of Dose-Intensity Chemotherapy in Cancer Patients,” Journal of Clinical Oncology, Vol. 24, No. 12, 2006, pp. 1852-1859. doi:10.1200/JCO.2005.04.2838
C. H. Lin, W. C. Lu, C. W. Wang, Y. C. Chan and M. K. Chen, “Capsaicin Induces Cell Cycle Arrest and Apoptosis in Human KB Cancer Cells,” BMC Complementary and Alternative Medicine, Vol. 13, No. 1, 2013, pp. 46. doi:10.1186/1472-6882-13-46
D. J. Morré, S. Caldwell, A. Mayorga, L. Y. Wu and D. M. Morre, “NADH Oxidase Activity from Sera Altered by Capsaicin is Widely Distributed among Cancer Patients,” Archives of Biochemistry and Biophysics, Vol. 342, No. 2, 1997, pp. 224-230. doi:10.1006/abbi.1997.0110
A. Mori, S. Lehmann, J. O’Kelly, T. Kumagai, J. C. Desmond, M. Pervan, W. H. McBride, M. Kizaki and H. P. Koeffler, “Capsaicin, a Component of Red Peppers, Inhibits the Growth of Androgen-Independent, p53 Mutant Prostate Cancer Cells,” Cancer Research, Vol. 66, No. 6, 1996, pp. 3222-3229. doi:10.1158/0008-5472.CAN-05-0087
P. S. Patel, M. L. Varney, B. J. Dave and R. K. Singh, “Regulation of Constitutive and Induced NF-kappaB Activation in Malignant Melanoma Cells by Capsaicin Modulates Interleukin-8 Production and Cell Proliferation,” Journal of Interferon & Cytokine Research, Vol. 22, No. 4, 2002, pp. 427-435. doi:10.1089/10799900252952217
P. S. Patel, S. Yang, A. Li, M. L. Varney and R. K. Singh, “Capsaicin Regulates Endothelial Cell Growth Factor Expression by Modulation of Hypoxia Inducing Factor1-Alpha in Human Malignant Melanoma Cells,” Journal of Cancer Research and Clinical Oncology, Vol. 129, No. 9, 2002, pp. 461-468. doi:10.1007/s00432-002-0368-8
X. F. Gong, M. W. Wang and T Ikejima, “Mechanisms of Capsaicin-Induced Apoptosis of Human Melanoma A375-S2 Cells,” Zhonghua Zhong Liu Za Zhi, Vol. 27, No. 7, 2005, pp. 401-403.
H. J. Kang, Y. Soh, M. S. Kim, E. J. Lee, Y. J. Surh, H. R. Kim, S. H. Kim and A. Moon, “Roles of JNK-1 and p38 in Selective Induction of Apoptosis by Capsaicin in Ras-Transformed Human Breast Epithelial Cells,” International Journal of Cancer, Vol. 103, No. 4, 2003, pp. 475-482. doi:10.1002/ijc.10855
Y. J. Surh, “More Than Spice: Capsaicin in Hot Chilli Peppers Makes Tumor Cells Commit Suicide,” Journal of the National Cancer Institute, Vol. 94, No. 17, 2002, pp. 1263-1265. doi:10.1093/jnci/94.17.1263
H. S. Jun, T. Park, C. K. Lee, M. K. Kang, M. S. Park, H. I. Kang, Y. L. Surh and O. H. Kim, “Capsaicin Induced Apoptosis of B16-F10 Melanoma Cells through DownRegulation of Bcl-2,” Food Chem Toxicol , Vol. 45, No. 5, 2007, pp. 708-715. doi:10.1016/j.fct.2006.10.011
M. Y. Jung, H. J. Kang and A. Moon, “Capsaicin-Induced Apoptosis in SK-Hep1 Hepatocarcinoma Cell Involves Bcl-2 Down-Regulation and Caspase-3 Activation,” Cancer Letters, Vol. 165, No. 2, 2001, pp. 139-145. doi:10.1016/S0304-3835(01)00426-8
M. Bhutani, A. K. Pathak, A. S. Nair, A. B. Kunnumakkara, S. Guha, G. Sethi and B. B. Aggarwal, “Capsaicin Is a Novel Blocker of Constitutive and Interleukin-6-Inducible STAT3 Activation,” Clinical Cancer Research, Vol. 13, No. 10, 2007, pp. 3024-3032. doi:10.1158/1078-0432.CCR-06-2575
E. Bodó, I. Kovács, A. Telek, A. Varga, R. Paus, L. Kovácsa and T. Bíró, “Vanilloid Receptor-1 (VR1) Is Widely Expressed on Various Epithelial and Mesenchymal Cell Types of Human Skin,” Journal of Investigative Dermatology, Vol. 123, No. 2, 2004, pp. 410-413. doi:10.1111/j.0022-202X.2004.23209.x
C. S. Kim, W. H. Park, J. Y. Park, J. H. Kang, M. O. Kim, T. Kawada, H. Yoo, I. S. Han and R. Yu, “Capsaicin, a Spicy Component of Hot Pepper, Induces Apoptosis by Activation of the Peroxisome Proliferators-Activated Receptor Gamma in HT-29 Human Colon Cancer Cells,” Journal of Medicinal Food, Vol. 7, No. 3, 2004, pp. 267-273.
J. L. Wang, D. Liu, Z. J. Zhang, S. Shan, X. Han, S. M. Sinivasula, C. M. Croce, E. S. Alnemri and Z. Huang, “Structure-Based Discovery of an Organic Compound that Binds Bcl-2 Protein and Induces Apoptosis of Tumor Cells,” Proceeding of National Acadamiy Sciences of the United State of America, Vol. 97, No. 13, 2000, pp. 7124-7129. doi:10.1073/pnas.97.13.7124
C. Campàs, A. M. Cosialls, M. Barragán, D. IglesiasSerret, A. F. Santidrián, L. Coll-Mulet, M de Frias, A. Domingo, G. Pons and J. Gil, “Bcl-2 Inhibitors Induce Apoptosis in Chronic Lymphocytic Leukemia Cells”, Experimental Hematology, Vol. 34, No. 12, 2006, pp. 1663-1669. doi:10.1016/j.exphem.2006.07.008
S. Mena, M. Benlloch, A. Ortega, J. Carretero, E. Obrador, M. Asensi, I. Petchen, B. D. Brown and J. M. Estrella, “Bcl-2 and Glutathione Depletion Sensitizes B16 Melanoma to Combination Therapy and Eliminates Metastatic Disease,” Clinical Cancer Research, Vol. 13, No. 9, 2007, pp. 2658-2666. doi:10.1158/1078-0432.CCR-06-2642
L. Dal Lago, V. D’Hondt and A. Awada, “Selected Combination Therapy with Sorafenib: A Review of Clinical dAta and Perspectives in Advanced Solid Tumors,” Oncologist, Vol. 13, No. 8, 2008, pp. 845-858. doi:10.1634/theoncologist.2007-0233
K. Y. Woo, L. K. Abbot and L. Linrach, “Evidence-Based Approach to Manage Persistent Wound-Related Pain,” Current Opinion in Supportive and Palliative Care, Vol. 7, No. 1, 2013, pp. 86-94. doi:10.1097/SPC.0b013e32835d7ed2
A. Leiherer, A. Mündlein and H. Drexel, “Phytochemicals and Their Impact on Adipose Tissue Inflammation and Diabetes,” Vascular Pharmacology, Vol. 58, No. 1-2, 2012, pp. 3-20. doi:10.1016/j.vph.2012.09.002
M. P. Flores, A. P. Castro and J. dos S. Nascimento, “Topical Analgesics,” Revista Brasileira de Anestesiologia, Vol. 62, No. 2, 2012, pp. 244-252. doi:10.1590/S0034-70942012000200010
P. Anand and K. Bley, “Topical Capsaicin for Pain Management: Therapeutic Potential and Mechanisms of Action of the New High-Concentration Capsaicin 8% Patch,” British Journal of Anaesthesia, Vol. 107, No. 4, 2011, pp. 490-502. doi:10.1093/bja/aer260
S. Chrubasik, T. Weiser and B. Beime, “Effectiveness and Safety of Topical Capsaicin Cream in the Treatment of Chronic Soft Tissue Pain,” Phytotherapy Research, Vol. 24, No. 12, 2012, pp. 1877-1885. doi:10.1002/ptr.3335
F. J. Silvestre, J. Silvestre-Rangil, J. C. Tanarit-Santafé and D. Bautista, “Application of a Capsaicin Rinse in the Treatment of Burning Mouth Syndrome,” Medicina Oral Patologia Oral y Cirugia Bucal, Vol. 17, No. 1, 2012, pp. 1-4. doi:10.4317/medoral.17219
C. T. Hartrick, C. Pestano, N. Carlson and S. Hartrick, “Capsaicin Instillation for Postoperative Pain Following Total Knee Arthroplasty: A Preliminary Report of a Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicentre Trial,” Clinical Drug Investigation, Vol. 31, No. 12, 2011, pp. 877-882. doi:10.1007/BF03256925
R. Baron and F. Mahn, “Types of Topical Treatment for Peripheral Neuropathic Pain: Mechanism of Action and Indications,” Schmerz, Vol. 24, No. 4, 2012, pp. 317-325. doi:10.1007/s00482-010-0939-6
A. K. Ghosh and S. Basu, “Tumor Macrophages as a Target for Capsaicin Mediated Immunotherapy,” Cancer Letters, Vol. 324, No. 1, 2012, pp. 91-97. doi:10.1016/j.canlet.2012.05.002
C. Hall, S. M. Troutman, D. K. Price, W. D. Figg and M. H. Kang, “Bcl-2 Family of Proteins as Therappeutic Targets in Genitourinary Neoplasms,” Clinical Genitourinary Cancer, Vol. 11, No. 1, 2013, pp. 9-10. doi:10.1016/j.clgc.2012.09.002
M. H. Kang and C. P. Reynolds, “Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy,” Clinical Cancer Research, Vol. 15, No. 4, 2009, pp. 1126-1132. doi:10.1158/1078-0432.CCR-08-0144
R. Yamaguchi, E. Janssen, G. Perkins, M. Ellisman, S. Kitada and J. C. Reed, “Efficient Elimination of Cancer Cells by Deoxyglucose-ABT-263/737 Combination Therapy,” PLoS One, Vol. 6, No. 9, 2011, pp. 1-14. doi:10.1371/journal.pone.0024102
M. J. Iadarola and A. J. Mannes, “The Vanilloid Resiniferatoxin for Interventional-Based Pain Control,” Current Topics in Medicinal Chemistry, Vol. 11, No. 17, 2011, pp. 2171-2179. doi:10.2174/156802611796904942