ABSTRACT
OBJECTIVE: Over-expression of COX-2 has been linked with various molecular signaling such as carcinogenesis, invasiveness, and malignant tumour metastasis. Besides, the use of celecoxib is also related to lowering the risk of breast cancer. This study therefore designed to explore the synergistic inhibitory effect of the combination of curcumin and celecoxib on the growth of human breast cancer cells. MATERIALS AND METHODS: In our investigation, we treated MDA-MB-231 cancer cells with different concentrations of curcumin and celecoxib. The enzyme-linked immunoassay was used to measure the COX-2 expression levels. MDA-MB-231 growth was examined by MTS cell viability assay, and synergy detection was carried out using combination index approaches. The drug-likeliness of the tested drugs (curcumin and celecoxib) were computed and predicted ADME pharmacokinetic parameters by in silico. Further, we have conducted BOILED-Egg plot and bioavailability radar analysis for the curcumin and celecoxib. RESULTS: The result of the physicochemical and ADMET/pharmacokinetic properties showed that these two drugs have good oral and optically bioavailable absorption. The present in silico study could offer a reliable theoretical basis for future structural modification of these compounds to treat breast cancer. The in vitro results suggested that curcumin and celecoxib individually inhibited the growth of MDA-MB-231 cells in a dose-dependent manner. The effect was synergistic for MDA-MB-231 cells relative to the two compounds individually. The synergistic growth inhibitory effect was mediated by a mechanism that possibly involves inhibition of the COX-2 pathways. CONCLUSIONS: Our findings show the prominent anti-proliferative effects of celecoxib and/or curcumin on MDA-MB-231 cells, providing a rationale for further detailed preclinical and potential clinical studies of this combination for breast cancer therapy. Further, these computed parameters suggested that curcumin possesses a high tendency to act as an adjuvant drug with celecoxib in the treatment of breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , Celecoxib/pharmacology , Curcumin/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Celecoxib/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Curcumin/chemistry , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemistry , Drug Screening Assays, Antitumor , Drug Therapy, Combination , Female , Humans , Tumor Cells, CulturedABSTRACT
The pentane extract of the Peruvian plant, Lepidium meyenii (Maca), has been demonstrated to possess neuroprotective activity in previous in vitro and in vivo studies (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77-85, 2010; Pino-Figueroa et al. in Am J Neuroprot Neuroregener 3:87-92, 2011). This extract contains a number of macamides that may act on the endocannabinoid system (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77-85, 2010; Pino-Figueroa et al., 2011; Dini et al. in Food Chem 49:347-349, 1994). The aim of this study was to characterize the inhibitory activity of four of these maccamides (N-benzylstearamide, N-benzyloleamide, N-benzyloctadeca-9Z,12Z-dienamide, and N-benzyloctadeca-9Z,12Z,15Z-trienamide) on fatty acid amide hydrolase (FAAH), an enzyme that is responsible for endocannabinoid degradation in the nervous system (Kumar et al. in Anaesthesia 56:1059-1068, 2001). The four compounds were tested at concentrations between 1 and 100 µM, utilizing an FAAH inhibitor screening assay. The results demonstrated concentration-dependent FAAH inhibitory activities for the four macamides tested. N-Benzyloctadeca-9Z,12Z-dienamide demonstrated the highest FAAH inhibitory activity whereas N-benzylstearamide had the lowest inhibitory activity. In addition, N-benzylstearamide, N-benzyloleamide, and N-benzyloctadeca-9Z,12Z-dienamide demonstrated time-dependent inhibition when tested after a pre-incubation period, indicating that the mechanism of inhibition for these compounds most likely is irreversible. Of interest, unsaturation in the fatty acid moiety resulted in greater FAAH inhibitory activity. LC/MS/MS analysis demonstrated that FAAH was able to hydrolyze N-benzyloctadeca-9Z,12Z-dienamide, suggesting that N-benzyloctadeca-9Z,12Z-dienamide is also a slow substrate for FAAH. These results provide useful information about the mechanism of action of Lepidium meyenii and may help with the development of new compounds with FAAH inhibitory or modulatory activity.
