Amelioration of immune cell number depletion and potentiation of depressed detoxification system of tumor-bearing mice by curcumin
Introduction
Over the years, cancer therapy has witnessed many exciting developments, but a non-toxic approach clearly evades us still today. Although effective chemopreventive agents can induce cancer cell killing, their effects should be cell type specific, with tumor cells responding differently to their non-tumorigenic counterparts. It is known that the developing tumor causes immunosupression [1], [2] in host. Furthermore, side effects of chemotherapeutics include toxicity to bone marrow and the gastrointestinal tract, dermatological toxicity, cardiotoxicity, and asthenia [3]. Selective targeting and low toxicity for normal host tissues are, therefore fundamental requisites for ideal chemopreventive agents since a non-selective mechanism of action may lead to potentially severe immune toxicity [3], [4], [5]. However, lack of cancer-specific targets is perhaps the most significant problem [6]. Most of the available modalities of cancer therapy have their side effects. In fact, during the regimen of cancer chemotherapy various popular and effective drugs in use these days exert concurrent toxic manifestations including oxidative stress and liver damage in tumor-bearer [7], [8]. Well-known anti-cancer drugs, e.g., tamoxifen, dexamethasone, cyclophosphamide and methylpredinosolone have been reported to induce leukopenia and other toxic manifestation to the host [4], [5], [6], [8].
Besides immunosuppression, decreases in hepatic drug-metabolizing enzymes [9], anti-oxidants like superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST) and depletion in the level of non-enzymic anti-oxidants like reduced glutathione (GSH) are observed with tumor progression [10]. As a result, glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT) and alkaline phosphatase (ALP) are often elevated in the serum [11] indicating tumor-induced general toxicity of the host. In addition, during anti-tumor treatment various popular drugs exert toxicity in the host and oxygen-derived free radicals are probable mediators of such toxicity [8]. They are also implicated in many disease processes including carcinogenesis [12]. These associated toxicities, often defeat the purpose of providing relief from the disease as more often cancer patients suffer more from the side effects of the chemotherapeutic agents rather than the disease itself. Thus, although a therapeutic window might be achieved, toxicity to normal cells will continue to limit chemotherapy of cancer, unless new treatment paradigms are developed [13]. The answer to all these problems lies in some sort of therapy that might minimize the associated toxic effects and destroy tumor cells preferentially.
In this regard, medicinal plants have attracted interest of cancer scientists [14]. Thompson et al., [15] have demonstrated that consumption of fruits and vegetables reduced oxidative cellular damage. Thus, dietary substances, mainly from plant origin are likely to be important sources of agents that can modulate programmed cell death (apoptosis) in cancer cells. However, most of these compounds are not devoid of toxicity. Curcumin (diferuloylmethane), the active component of turmeric (Curcuma longa Linn), has been widely used as an anti-inflammatory, anti-oxidant and chemotherapeutic agent [16]. It has been recognized for the chemopreventive properties in breast, skin and forestomach carcinogenesis [17], [18]. Interestingly, turmeric has been used in large quantity as a condiment for thousands of years with no adverse reactions, thereby indicating its candidacy as probable non-toxic, anti-cancer agent [17]. This active phytochemical has an immunomodulatory property and stimulates macrophage phagocytic activity [19]. It inhibits production of pro-inflammatory cytokines, including IL-8, by tumor cells and modulates lymphocyte-mediated immune functions by increasing mucosal T and B cells [20], [21]. Curcumin protects thymocytes from dexamethasone-induced apoptosis [22]. It is also able to effectively quench singlet oxygen at very low concentration in aqueous systems and is a powerful inhibitor of hydrogen peroxide damage in human keratinocytes and fibroblasts [23], [24].
The role of free radicals in cancer and disease is well documented [7], [12]. Recent reports show that glutathione, an intracellular anti-oxidant, plays important role in the detoxification of carcinogens in head and neck cancer patients [25] and curcumin induces glutathione S-transferase and stimulates the detoxification system [26], [27]. A strict resemblance also exists between the mechanisms of the rapid superoxide radical decay caused by curcumin and that involved in the presence of the superoxide dismutase enzyme [28]. Restoration of these intrinsic Phase-I biotransformation and Phase-II detoxifying enzymes of the tumor-bearing host by curcumin definitely ameliorates the cytotoxicity of the developing tumor in the host. Addressing all these issues, we examined whether curcumin could induce differential effects in tumor cells and normal cells of the host. This could have great significance in the area of cancer therapy.
Section snippets
Animal and tumor model
All animal experiments were performed following ‘Principles of laboratory animal care’ (NIH publication no. 85-23, revised in 1985) as well as specific Indian laws on ‘Protection of Animals’ under the prevision of authorized investigators. Swiss albino mice (∼20 g each; 10–12 weeks old; 10 mice in each group) were randomly divided into four groups including: (i) normal set; (ii) curcumin-treated set; (iii) tumor-bearing set (intra-peritoneally injected with 1 × 106 exponentially grown Ehrlich's
Regression of Ehrlich's ascites carcinoma growth by curcumin
We evaluated the effect of curcumin on the numbers of Ehrlich's ascites carcinoma in tumor bearing Swiss albino mice. Administration of curcumin 1 week after EAC inoculation decreased the tumor cell number over their untreated counterpart (p < 0.001). It was observed that curcumin lessened tumor burden considerably in a dose-dependent manner showing optimum activity at doses of 37.5–50 mg/kg-body weights. At day 21 a total of 390 million EACs were measured in the peritoneal fluid of untreated mice,
Discussion
Dietary agents that interfere with tumor development at the stages of promotion and progression, in particular, are of potential clinical value [14], [15]. Since many chemopreventative agents have to be administered over a long period of time to establish their efficacy in humans, it is of paramount importance to establish their lack of toxicity. We have already reported that curcumin induces apoptosis in Ehrlich's ascites carcinoma cells [30]. Here we report that the developing tumor caused
Acknowledgements
Authors want to thank Mr. UK Ghosh and Mr. R Dutta for technical assistance. This work has been supported by research grants from CSIR and ICMR Govt. of India.
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