Elsevier

Pharmacological Research

Volume 50, Issue 5, November 2004, Pages 487-498
Pharmacological Research

The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of doxorubicin?

https://doi.org/10.1016/j.phrs.2004.04.002Get rights and content

Abstract

The potential anti-tumour activity of non-steroidal anti-inflammatory drugs (NSAIDS) has been previously discussed. This study was undertaken to assess the possible anti-tumour activity of the cyclooxygenase-2 (COX-2) inhibitor; celecoxib in an animal model of mammary carcinoma; the solid Ehrlich carcinoma (SEC). The possibility that celecoxib may modulate the anti-tumour activity of doxorubicin on the SEC was also studied. Some of the possible mechanisms underlying such modulation were investigated. The anti-tumour activity of celecoxib (25  mg kg−1), diclofenac (12.5  mg kg−1) and doxorubicin (2  mg kg−1) either alone or in combination were investigated on SEC in vivo through the assessment of tumour growth delay (TGD) and tumour volume (TV), changes in tumour DNA content and nitric oxide (NO) levels, immunohistochemical staining of the tumour suppressor gene product; p53 histopathological examination and determination of apoptotic index of SEC. In addition, the influence of these drugs on the DNA fragmentation pattern of Ehrlich carcinoma cells (ECC) was studied. It was found that both celecoxib and diclofenac lack the anti-tumour activity on SEC. In addition there was a significant increase in doxorubicin anti-tumour activity when administered in combination with celecoxib. Moreover, it was found that both celecoxib and diclofenac have the potential to inhibit the function of P-glycoprotein (P-gp) in ECC using rhodamine uptake and efflux assays. Therefore, the current study suggested the chemosensitizing potential of celecoxib in the SEC animal model of mammary tumour, which could be explained in part on the basis of inhibition of P-gp function, with possible enhancement of doxorubicin anti-tumour activity.

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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