Abstract
Social stressors evolving from individual and population interactions produce stress reactions in many organisms (including humans), influencing homeostasis, altering the activity of the immunological system, and thus leading to various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) in cancer promotion and to assess oxidative stress outcomes in terms of various in vivo biochemical parameters, oxidative stress markers, DNA damage, and the development of skin tumors in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz(a)anthracene (DMBA) alone (topical), and DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical) and exposure to CUS prior to DMBA or DMBA-TPA treatments and sacrificed after 16 weeks of treatment. Prior exposure to CUS significantly increased the pro-oxidant effect of carcinogen, depicted by compromised levels of antioxidants in the circulation and skin, accompanied by enhanced lipid peroxidation, plasma corticosterone, and marker enzymes as compared to DMBA-alone or DMBA-TPA treatments. DNA damage results corroborated the above biochemical outcomes. Also, the development of skin tumors (in terms of their incidence, tumor yield, and tumor burden) in mice in the presence and absence of stress further strongly supported our above biochemical measurements. CUS may work as a promoter of carcinogenesis by enhancing the pro-oxidant potential of carcinogens. Further studies may be aimed at the development of interventions for disease prevention by identifying the relations between psychological factors and DNA damage.
Similar content being viewed by others
References
Adachi S, Kawamura K, Takemoto K (1993) Oxidative damage of nuclear DNA in liver of rats exposed to psychological stress. Cancer Res 53:4153–4155
Ader R (2006) Psychoneuroimmunology, 4th edn. Academic, San Diego
Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, Stefanek M, Sood AK (2006) The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6(3):240–248
Arciszewska LK, Martin SE, Milner JA (1982) The antimutagenic effect of selenium on 7,12-dimethylbenz(a)anthracene and metabolites in the ames Salmonella/microsome system. Biol Trace Elem Res 4(4):259–267
Armstrong JS, Steinauer KK, Hornung B, Irish JM, Lecane P, Birrell GW, Peehl DM, Knox SJ (2002) Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ 9:252–263
Besedovsky HO, Normann S, Schardt M, Del RA (2000) Endocrine host responses during early and late phases of tumor development. Int J Cancer 86:457–461
Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310
Camhi SL, Alam J, Wiegand GW, Chin BY, Choi AMK (1998) Transcriptional activation of the HO-1 gene by lipopolysaccharide is mediated by 5′ distal enhancers: role of reactive oxygen intermediates and AP-1. Am J Respir Cell Mol Biol 18:226–234
Carlberg I, Mannervik B (1975) Purification and characterization of the flavoenzyme glutathione reductase from rat liver. J Biol Chem 250:5475–5480
Claiborne A (1985) Catalase activity. In: Green Wald RA (ed) CRC handbook of methods for oxygen radical research. CRC Press, Boca Raton, pp 283–284
Conney AH (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons, Clowes GHA memorial lecture. Cancer Res 4:4875–4917
Das UN (2002) A radical approach to cancer. Med Sci Monit 8:79–92
Dhabhar FS, McEwen BS (2006) Bidirectional effects of stress on immune function: possible explanations for salubrious as well as harmful effects. In: Ader R (ed) Psychoneuroimmunology, 4th edn. Elsevier, San Diego
Dhabhar FS, Miller AH, McEwen BS, Spencer RL (1995) Effects of stress on immune cell distribution—dynamics and hormonal mechanisms. J Immunol 54:5511–5527
Dhabhar FS, Miller AH, Stein M et al (1994) Diurnal and stress-induced changes in distribution of peripheral blood leukocyte subpopulations. Brain Behav Immun 8:66–79
Donovan PJ, Smith GT, Nardone R (2004) The mutagenic effects of 7,12-dimethylbenz[a]anthacene, 3-methylcholanthrene and benzo[a]pyrene to the developing Syrian hamster fetus measured by an in vivo/in vitro mutation assay. Mutat Res 554(1–2):111–120
Dreher D, Junod AF (1996) Role of oxygen free radicals in cancer development. Eur J Cancer 32A:30–38
Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95
Dvorak Z, Pavek P (2010) Regulation of drug-metabolizing cytochrome P450 enzymes by glucocorticoids. Drug Metab Rev 42:621–635
Eden WV, Spiering R, Broere F, van der Zee R (2012) A case of mistaken identity: HSPs are no DAMPs but DAMPERs. Cell Stress Chaperones 17(3):281–292
Feder ME, Hofmann GE (1999) Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annu Rev Physiol 61:243–282
Feig DI, Reid TM, Loeb LA (1994) Reactive oxygen species in tumorigenesis. Cancer Res 54:1890s–1894s
Flint M, McCarty K, Jenkins F, Conrads T, Sun M, Baum A (2011) Psychological stress accelerates the onset of tumor formation and alters the type and location of tumors in a DMBA mouse carcinogenesis model. Stress Health 27:e129–e138
Friesen C, Kiess Y, Debatin KM (2004) A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death Differ 11(Suppl 1):S73–S85
Garmyn M, Degreef H (1997) Suppression of UVB-induced c-fos and c-jun repression in human keratinocytes by N-acetylcysteine. J Photochem Photobiol B37:125–130
Glaser R, Kiecolt-Glaser JK (2005) Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5:243–251
Guerin MR (1978) Energy sources of polycyclic aromatic hydrocarbons. In: Gelboin HV, Ts’o POP (eds) Polycyclic hydrocarbons and cancer: chemistry, molecular biology and environment. Academic, New York, pp 1–42
Guyton KZ, Kensler TW (1993) Oxidative mechanisms in carcinogenesis. Br Med Bull 49:523–544
Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione-S-transferases: the first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139
Joels M, Karst H, Krugers HJ, Lucassen PJ (2007) Chronic stress: implications for neuronal morphology, function and neurogenesis. Front Neuroendocrinol 28:72–96
Jollow DJ, Mitchell JR, Zampaglione N, Gillete JR (1974) Bromobenzene induced liver necrosis: protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic intermediate. Pharmacology 11:151–169
Jones Q, Voegeli TS, Li G et al (2011) Heat shock proteins protect against ischemia and inflammation through multiple mechanisms. Inflamm Allergy Drug Targets 10(4):247–259
Katz RJ, Roth KA, Carroll BJ (1981) Acute and chronic effects on open field activity in the rat: implications for a model of depression. Neurosci Biobehav Rev 5:247–251
Kim SO, Kundu JK, Shin YK, Park JH, Cho MH, Kim TY, Surh YJ (2005) Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-kappaB in phorbol ester-stimulated mouse skin. Oncogene 24:2558–2567
Kulesz-Martin MF (1997) Biological aspects of multistage carcinogenesis as studied in experimental animals and in cell culture models, In: Sipes IG, Charlene A, McQueen AJ (ed) Chemical carcinogens and anticarcinogens. Comprehensive Toxocology 12:7–30
La E, Muga SJ, Locniskar MF, Fischer SM (1999) Altered expression of interleukin-1 receptor antagonist in different stages of mouse skin carcinogenesis. Mol Carcinog 24:276–286
Liu J, Mori A (1999) Stress, aging and oxidative damage. Neurochem Res 24:1479–1497
Locigno R, Castronovo V (2001) Reduced glutathione system; role of cancer development, prevention and treatment (Review). Int J Oncol 19:221–236
Locke M, Noble EG, Atkinson BG (1990) Exercising mammals synthesize stress proteins. Am J Physiol 258(4):C723–C729
Lowry OH, Rosenberg NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275
Marklund S, Marklund G (1974) The involvement of the superoxide anion radical in the auto oxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474
McIntosh LJ, Sapolsky RM (1996) Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture. Exp Neurol 141:201–206
Miyata M, Furukawa M, Takahashi K, Gonzales FJ, Yamazoe Y (2001) Mechanism of 7,12-dimethylbenz(a)anthracene-induced immunotoxicity: role of metabolic activation at the target organ. Jpn J Pharmacol 86:302–309
Morano KA, Thiele DJ (1999) Heat shock factor function and regulation in response to cellular stress, growth, and differentiation signals. Gene Expr 7(4–6):271–282
Muqbil I, Azmi AS, Banu N (2006) Prior exposure to restraint stress enhances 7,12-dimethylbenz(a)anthracene (DMBA) induced DNA damage in rats. FEBS Lett 580:3995–3999
Muqbil I, Banu N (2006) Enhancement of pro oxidant effect of dimethylbenz (a) anthracene (DMBA) in rats by pre exposure to restraint stress. Cancer Lett 240:213–220
Noble EG, Milne KJ, Melling CWJ (2008) Heat shock proteins and exercise: a primer. Appl Physiol Nutr Metab 33(5):1050–1065
Oberley TD, Oberley LW (1993) Oxygen radicals and cancer. In: Yu BP (ed) Free radicals in aging. CRC Press, Boca Raton, pp 247–267
Perez-Nievas BG, Garcia-Bueno B, Caso JR, Menchen L, Leza JC (2007) Corticosterone as a marker of susceptibility to oxidative/nitrosative cerebral damage after stress exposure in rats. Psychoneuroendocrinology 32:703–711
Pompella A, Corti A, Paolicchi A, Giommarelli C, Zunino F (2007) Gamma-glutamyltransferase, redox regulation and cancer drug resistance. Curr Opin Pharmacol 7:360–366
Powell ND, Tarr AJ, Sheridan JF (2013) Psychosocial stress and inflammation in cancer. Brain Behav Immun 30(Suppl):S41–S47
Pradhan SN, Prabhati R (1974) Effects of stress on growth of transplanted and 7,12-dimethylbenz (a) anthracene induced tumors and their modification by psychotropic drugs. J Natl Inst 53:1241–1245
Radons J, Multhoff G (2005) Immunostimulatory functions of membrane-bound and exported heat shock protein 70. Exerc Immunol Rev 11:17–33
Saul AN, Oberyszyn TM, Daugherty C et al (2005) Chronic stress and susceptibility to skin cancer. J Natl Cancer Inst 97:1760–1767
Shah SV, Kempson SA, Northrup TE, Dousa TP (1979) Renal adaptation to low phosphate diet in rats. J Clin Invest 64:955–966
Shavit J, Lewis LW, Ferman GW, Gale RP, Liebeskind JC (1983) Endogenous opioids may mediate the effects of stress on tumor growth and immune function. Proc West Pharmacol Soc 26:53–56
Shields AM, Panayi GS, Corrigall VM (2012) A new-age for biologic therapies: long-term drug-free therapy with BiP? Front Immunol 3:17
Simmons HF, James RC, Harbison RD, Patel DG, Roberts SM (1991) Examination of the role of catecholamines in hepatic glutathione suppression by cold-restraint in mice. Toxicology 67:29–40
Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191
Sklar LS, Anisman H (1979) Stress and coping factors influence tumor growth. Science 205:513–515
Steplewski Z, Goldman PR, Vogel WH (1987) Effect of housing stress on the formation and development of tumors in rats. Cancer Lett 34:257–261
Steplewski Z, Vogel WH, Ehya H, Poropatich C, McDonald-Smith J (1985) Effect of restraint stress on inoculated tumor growth and immune response in rats. Cancer Res 45:5128–5133
Stone K, Ksebati M, Marnett LJ (1990) Investigation of the adducts formed by reaction of malondialdehyde with adenosine. Chem Res Toxicol 3:33–38
Suhail N, Bilal N, Hasan S, Banu N (2011) Chronic unpredictable stress exacerbates 7,12-dimethylbenz (a) anthracene induced hepatotoxicity and nephrotoxicity in Swiss albino mice. Mol Cell Biochem 355:117–126
Teoh ML, Fitzgerald MP, Oberley LW, Domann FE (2009) Over expression of extracellular superoxide dismutase attenuates heparanase expression and inhibits breast carcinoma cell growth and invasion. Cancer Res 69:6355–6363
Wijnhoven SW, Kool HJ, Mullenders LHF, Slater R, Van Zeeland AA, Vrieling H (2001) DMBA-induced toxic and mutagenic response vary dramatically between NER-deficient Xpa, Xpc and Csb mice. Carcinogenesis 22:1099–1106
Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 93:358–364
Woodward CJ, Emery PW (1987) Determination of plasma corticosterone using high-performance liquid chromatography. J Chromatogr 419:280–284
Yang PC, Tu YH, Perdue MH, Oluwole C, Struiksma S (2009) Regulatory effect of heat shock protein 70 in stress-induced rat intestinal epithelial barrier dysfunction. N Am J Med Sci 1(1):9–15
Acknowledgments
Thanks are due to University Grants Commission (UGC), New Delhi, for financial support to the author (N. Suhail) in the form of a scholarship. The authors are grateful to UGC-SAP (Special Assistance Programme), DST-FIST (Department of Science and Technology), and Aligarh Muslim University for the facilities.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Suhail, N., Bilal, N., Hasan, S. et al. Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12-dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice. Cell Stress and Chaperones 20, 1023–1036 (2015). https://doi.org/10.1007/s12192-015-0632-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-015-0632-x