The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of doxorubicin?
Introduction
The chemotherapeutic and chemoprophylactic potentials of non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested. The anti-tumour activity of NSAIDS [1], [2], [3], [4] and selective cyclooxygenase-2 (COX-2) inhibitors [5], [6], [7], [8], [9], [10] were reported against a variety of tumour cell lines including breast, colorectal, lung, prostate, esophageal and pancreatic carcinomas. These anti-tumour effects have been reported to be via both cyclooxygenase (COX)-dependent and COX-independent mechanisms [11], [12], [13], [14], [15], [16], [17], [18].
Doxorubicin is a versatile anthracycline anti-tumour agent, which is effective against wide range of cancers including solid tumours, leukemias and lymphomas [19]. This anti-tumour activity of doxorubicin has been reported to be mediated through different mechanisms including inhibition of the nuclear enzyme DNA topisomerase II [20] inducing double-strand DNA breakage [21], [22], and generation of superoxide, hydrogen peroxide and hydroxyl radicals [23].
The efficacy of anthracyclines is greatly compromised by emergence of multiple drug resistance (MDR), which is considered as a major obstacle to successful cancer chemotherapy. Such resistance pattern is mediated by the MDR-1 gene, through its product; the P-glycoprotein (P-gp), where it has been suggested that P-gp confers multidrug resistance to cancer cells by extruding cytotoxic drugs, thus reducing their cytotoxicity [24], [25], [26], [27], [28]. It has been proposed that pretreatment with selective COX-2 inhibitors may be useful in the prevention of multidrug resistance in breast tumours [29].
Therefore, this study aimed at investigating the following: (1) the possible anti-tumour activity of selective COX-2 inhibitors such as celecoxib, and non-selective COX inhibitors such as diclofenac on the growth of solid Ehrlich carcinoma (SEC) (an animal model of mammary tumour). (2) The possibility that COX inhibitors may enhance the activity of cytotoxic drugs such as doxorubicin, and hence the possibility of their use as adjuvant therapy in the treatment of cancer. Some of the possible mechanisms of such interaction were also investigated.
Section snippets
Materials
Celecoxib was a kind gift from Amriya Drug Co. (Alexandria, Egypt), diclofenac was a kind gift from SEDICO (Egypt), doxorubicin was obtained from the commercially available Adriablastina® vials (Pharmacia & Upjohn, Italy). All other chemicals used were of the highest analytical purity.
Animals
Adult female Swiss albino mice weighing 18–20 g, were obtained from the animal house of the National Cancer Institute (NCI), Cairo University, Egypt. They were fed standard pellet chow and allowed free access to
Results
Mice received a single dose of celecoxib (25 mg kg−1) or diclofenac (12.5 mg kg−1) alone did not show significant TGD of SEC beyond the control group (Table 1). On the other hand, doxorubicin treatment (2 mg kg−1) resulted in significant TGD (3.9 days) of SEC beyond the control group.
Combination of doxorubicin with either celecoxib or diclofenac showed significant TGD (4.2 and 4 days, respectively) of SEC beyond the control group. However, these delays were not significant beyond the delay produced
Discussion
Data presented in this study showed that neither celecoxib nor diclofenac at the tested dose levels possesses anti-tumour activity on SEC as assessed by TGD and TV experiments. This was further verified by the analysis of the DNA content in the excised tumour masses where both treatments didn’t cause significant changes.
Histopathological examination of SEC sections further revealed that celecoxib and diclofenac did not show significant changes in apoptotic figures or bodies, suggesting that
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