Abstract
The present study was conducted to investigate if anti-inflammatory drug aspirin could alter the cytotoxic action of cisplatin on tumor cells. Using a transplantable T cell lymphoma in a murine model, we demonstrate that exposure to aspirin exerts a priming action on tumor cells, rendering them susceptible to induction of cell death by cisplatin with consequences on retardation of tumor progression. The priming action of aspirin on tumor cells was found to be dependent on an altered constitution of tumor microenvironment with respect to decline of acidosis and modulation in the expression of cell cycle and survival regulatory molecules like cyclin B1, cyclin D, bcl-2, bcl-xL, p53, and cytokines: IL-4, IL-10, IFN- γ & VEGF. The study also discusses possible mechanisms underlying augmentary action of aspirin on cisplatin-mediated tumor cells killing. This is the first report showing that pre-exposure of tumor cells to aspirin lowers the concentration of cisplatin to exert its cytotoxic action. The finding of this study will help in designing novel antitumor protocols with reduced dose of cisplatin.
Similar content being viewed by others
Abbreviations
- Asp:
-
Aspirin
- CP:
-
Cisplatin
- DL:
-
Dalton’s lymphoma
- DLAF:
-
DL ascitic fluid
- IFN-γ:
-
Interferon-gamma
- IL:
-
Interleukin
- i.p.:
-
Intraperitoneal
- HIF:
-
Hypoxia inducible factor
- MTT:
-
[3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide]
- NSAIDs:
-
Nonsteroidal anti-inflammatory drugs
- PI:
-
Propidium iodide
- SDS:
-
Sodium dodecyl sulfate
- VEGF:
-
Vascular endothelial growth factor
References
Fischer SM, Hawk ET, Lubet RA (2011) Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancer chemoprevention. Cancer Prev Res (Phila) 4:1728–1735
Flores-Santana W, Moody T, Chen W, Gorczynski MJ, Shoman ME et al (2011) Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells. Br J Pharmacol 165:1058–1067
Sun Y, Huang L, Mackenzie GG, Rigas B (2011) Oxidative stress mediates through apoptosis the anticancer effect of phospho-NSAIDs: implications for the role of oxidative stress in the action of anticancer agents. J Pharmacol Exp Ther 338:775–783
Cahoon E, Rajaraman P, Alexander B, Doody M, Linet M et al (2012) Use of non-steroidal anti-inflammatory drugs and risk of basal cell carcinoma in the United States radiologic technologists study. Int J Cancer 130:2939–2948
Ararat E, Sahin I, Altundag K (2011) Mechanisms behind the aspirin use and decreased breast cancer incidence. J BUON 16:180
Ashktorab H, Dawkins FW, Mohamed R, Larbi D, Smoot DT (2005) Apoptosis induced by aspirin and 5-fluorouracil in human colonic adenocarcinoma cells. Dig Dis Sci 50:1025–1032
Baigent C, Blackwell L, Collins R, Emberson J, Godwin J et al (2009) Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373:1849–1860
Baron JA (2009) Aspirin and NSAIDs for the prevention of colorectal cancer. Recent Results Cancer Res 181:223–229
Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Wu K et al (2008) Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology 134:21–28
McCarty MF, Block KI (2006) Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy. Integr Cancer Ther 5:252–268
Johnsen SP, Larsson H, Tarone RE, McLaughlin JK, Norgard B et al (2005) Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med 165:978–984
Bunimov N, Laneuville O (2008) Cyclooxygenase inhibitors: instrumental drugs to understand cardiovascular homeostasis and arterial thrombosis. Cardiovasc Hematol Disord Drug Targets 8:268–277
Manrique C, Lastra G, Palmer J, Gardner M, Sowers JR (2008) Aspirin and Diabetes Mellitus: revisiting an old player. Ther Adv Cardiovasc Dis 2:37–42
Kumar A, Vishvakarma NK, Tyagi A, Bharti AC, Singh SM (2012) Anti-neoplastic action of aspirin against a T-cell lymphoma involves an alteration in the tumour microenvironment and regulation of tumour cell survival. Biosci Rep 32:91–104
Vishvakarma NK, Kumar A, Singh V, Singh SM (2012) Hyperglycemia of tumor microenvironment modulates stage-dependent tumor progression and multidrug resistance: implication of cell survival regulatory molecules and altered glucose transport. Mol Carcinog doi:10.1002/mc.21922
Rabik CA, Dolan ME (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33:9–23
Kostova I (2006) Platinum complexes as anticancer agents. Recent Pat Anticancer Drug Discov 1:1–22
Araujo JG, Mota LG, Leite EA, Maroni Lde C, Wainstein AJ et al (2011) Biodistribution and antitumoral effect of long-circulating and pH-sensitive liposomal cisplatin administered in Ehrlich tumor-bearing mice. Exp Biol Med (Maywood) 236:808–815
Armitage JO, Vose JM, Weisenburger DD (2004) Towards understanding the peripheral T-cell lymphomas. Ann Oncol 15:1447–1449
Gupta V, Singh SM (2008) Gender dimorphism of tumor growth: role of gonadal hormones in differential regulation of apoptosis of a murine T cell lymphoma. J Biomed Sci 15:147–162
Singh V, Singh MP, Singh SM (2008) Cell density-dependent alterations in tumorigenic potential of a murine T-cell lymphoma: implication in the evolution of multidrug resistance in tumor cells. Anticancer Drugs 19:793–804
Singh V, Singh SM (2009) Progressive tumor growth-associated altered tumor microenvironment: implications in a tumor stage-dependent modulation in survival of a murine T cell lymphoma. J Cancer Res Clin Oncol 135:1015–1024
Singh V, Singh SM (2009) A tumour stage-dependent evolution of drug resistant T cell lymphoma: role of soluble mediators of tumour and host origin. Leuk Res 33:700–709
Vishvakarma NK, Kumar A, Singh SM (2011) Role of curcumin-dependent modulation of tumor microenvironment of a murine T cell lymphoma in altered regulation of tumor cell survival. Toxicol Appl Pharmacol 252:298–306
Vishvakarma NK, Singh SM (2011) Augmentation of myelopoiesis in a murine host bearing a T cell lymphoma following in vivo administration of proton pump inhibitor pantoprazole. Biochimie 93:1786–1796
Kumar R, Sodhi A, Singh SM (1993) Effect of in vivo administration of cisplatin on the colony forming ability of murine bone marrow cells. Int J Immunopharmacol 15:281–286
Verma VK, Singh V, Singh MP, Singh SM (2010) Treadmill exercise-dependent tumor growth retardation in T-cell lymphoma-bearing host displays gender dimorphism. Oncol Res 18:293–304
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Kusumbe AP, Bapat SA (2009) Cancer stem cells and aneuploid populations within developing tumors are the major determinants of tumor dormancy. Cancer Res 69:9245–9253
Somoza B, Guzman R, Cano V, Merino B, Ramos P et al (2007) Induction of cardiac uncoupling protein-2 expression and adenosine 5′-monophosphate-activated protein kinase phosphorylation during early states of diet-induced obesity in mice. Endocrinology 148:924–931
Mellor HR, Callaghan R (2011) Accumulation and distribution of doxorubicin in tumour spheroids: the influence of acidity and expression of P-glycoprotein. Cancer Chemother Pharmacol 68:1179–1190
Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10:767–777
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K et al (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490
Chiche J, Ilc K, Laferriere J, Trottier E, Dayan F et al (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69:358–368
Gillies RJ, Gatenby RA (2007) Hypoxia and adaptive landscapes in the evolution of carcinogenesis. Cancer Metastasis Rev 26:311–317
Semenza GL (2011) Hypoxia. Cross talk between oxygen sensing and the cell cycle machinery. Am J Physiol Cell Physiol 301:C550–C552
Rademakers SE, Lok J, van der Kogel AJ, Bussink J, Kaanders JH (2011) Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer 11:167
Maybin JA, Hirani N, Brown P, Jabbour HN, Critchley HO (2011) The regulation of vascular endothelial growth factor by hypoxia and prostaglandin Falpha during human endometrial repair. J Clin Endocrinol Metab 96:2475–2483
Weige CC, Allred KF, Armstrong CM, Allred CD (2011) P53 mediates estradiol induced activation of apoptosis and DNA repair in non-malignant colonocytes. J Steroid Biochem Mol Biol 128:113–120
Tagscherer KE, Fassl A, Sinkovic T, Combs SE, Roth W (2011) p53-dependent regulation of Mcl-1 contributes to synergistic cell death by ionizing radiation and the Bcl-2/Bcl-XL inhibitor ABT-737. Apoptosis 17:187–199
Sharma S, Stolina M, Lin Y, Gardner B, Miller PW et al (1999) T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function. J Immunol 163:5020–5028
Pangault C, Ame-Thomas P, Ruminy P, Rossille D, Caron G et al (2010) Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis. Leukemia 24:2080–2089
Hamidullah ChangkijaB, Konwar R (2011) Role of interleukin-10 in breast cancer. Breast Cancer Res Treat 133:11–21
Castillo R, Mascarenhas J, Telford W, Chadburn A, Friedman SM et al (2000) Proliferative response of mantle cell lymphoma cells stimulated by CD40 ligation and IL-4. Leukemia 14:292–298
Vishvakarma NK, Singh SM (2010) Immunopotentiating effect of proton pump inhibitor pantoprazole in a lymphoma-bearing murine host: implication in antitumor activation of tumor-associated macrophages. Immunol Lett 134:83–92
Alas S, Emmanouilides C, Bonavida B (2001) Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin’s lymphoma to apoptosis. Clin Cancer Res 7:709–723
Sun Y, Tang XM, Half E, Kuo MT, Sinicrope FA (2002) Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res 62:6323–6328
Yu J, Ren X, Li H, Cao S, Han Y et al (2011) Synergistic effect of CH-296 and interferon gamma on cytokine-induced killer cells expansion for patients with advanced-stage malignant solid tumors. Cancer Biother Radiopharm 26:485–494
Wu XH, Qian C, Yuan K (2011) Correlations of hypoxia-inducible factor-1alpha/hypoxia-inducible factor-2alpha expression with angiogenesis factors expression and prognosis in non-small cell lung cancer. Chin Med J (Engl) 124:11–18
Crasta JA, Mishra S, Vallikad E (2011) Ovarian serous carcinoma: relationship of p53 and bcl-2 with tumor angiogenesis and VEGF expression. Int J Gynecol Pathol 30:521–526
Lai Z, Kalkunte S, Sharma S (2011) A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice. Hypertension 57:505–514
Wilke CM, Wei S, Wang L, Kryczek I, Kao J et al (2011) Dual biological effects of the cytokines interleukin-10 and interferon-gamma. Cancer Immunol Immunother 60:1529–1541
Janardhanan R, Banik NL, Ray SK (2008) N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-gamma sensitivity for apoptosis in human glioblastoma cells. Cancer Lett 261:26–36
Barthson J, Germano CM, Moore F, Maida A, Drucker DJ et al (2011) Cytokines Tumor Necrosis Factor-alpha and Interferon-gamma Induce Pancreatic beta-Cell Apoptosis through STAT1-mediated Bim Protein Activation. J Biol Chem 286:39632–39643
Glover LE, Irizarry K, Scully M, Campbell EL, Bowers BE et al (2011) IFN-gamma attenuates hypoxia-inducible factor (HIF) activity in intestinal epithelial cells through transcriptional repression of HIF-1beta. J Immunol 186:1790–1798
Sn-Gl PL, Lp-Hn FJ, Lp-N JM, Morales AI (2011) An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity. Crit Rev Toxicol 41:803–821
Acknowledgments
Financial support to School of Biotechnology from DBT, New Delhi is acknowledged. The authors express gratitude to UGC-New Delhi for senior research fellowship support to Anjani Kumar. We are grateful to Dr. S. D. Singh, Parul Pathology Laboratory, Varanasi, India, for his kind help in various assays. Aspirin was obtained as a kind gift from Alta Laboratory (Mumbai, India).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kumar, A., Singh, S.M. Priming effect of aspirin for tumor cells to augment cytotoxic action of cisplatin against tumor cells: implication of altered constitution of tumor microenvironment, expression of cell cycle, apoptosis, and survival regulatory molecules. Mol Cell Biochem 371, 43–54 (2012). https://doi.org/10.1007/s11010-012-1421-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-012-1421-9