Tepoxalin

Effective cancer chemotherapy treatment requires both therapy delivery and retention by malignant cells. Cancer cell overexpression of the multidrug transmembrane transporter gene ABCB1 (MDR1, multi-drug resistance protein 1) thwarts therapy retention, leading to a drug-resistant phenotype. We explored the phenotypic impact of ABCB1 overexpression in normal human mammary epithelial cells (HMECs) via acute adenoviral delivery and in breast cancer cell lines with stable integration of inducible ABCB1 expression. One hundred sixty-two genes were differentially expressed between ABCB1-expressing and GFP-expressing HMECs, including the gene encoding the cyclooxygenase-2 protein, PTGS2. Several breast cancer cell lines with inducible ABCB1 expression demonstrated sensitivity to the 5-lipoxygenase, cyclooxygenase-1/2 inhibitor tepoxalin in two-dimensional drug response assays, and combination treatment of tepoxalin either with chemotherapies or with histone deacetylase (HDAC) inhibitors improved therapeutic efficacy in these lines. Moreover, selection for the ABCB1-expressing cell population was reduced in three-dimensional co-cultures of ABCB1-expressing and GFP-expressing cells when chemotherapy was given in combination with tepoxalin. Further study is warranted to ascertain the clinical potential of tepoxalin, an FDA-approved therapeutic for use in domesticated mammals, to restore chemosensitivity and improve drug response in patients with ABCB1-overexpressing drug-resistant breast cancers.

GC is associated with over expression of epidermal growth factor receptor (EGRF), Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX). We postulated that targeting these pathways will result in better treatment efficacy than using a single agent with higher dose which may cause toxicity and resistance. We evaluated Tepoxalin (TPX) a dual 5-LOX-COX inhibitor and Erlotinib (ERB) an EGFR inhibitor alone and combination in MGC-803 injected tumor xenografts mice. Female nude mice were selected and injected subcutaneously with MGC-803 GC cells and were grouped after the tumor model was formed. The treatment of TPX, ERB and their combination was given for 21 days. After treatment protocol proliferating index was measured, expression of apoptosis related proteins, 5-LOX, COX-2, EGFR, vascular endothelial growth factor-C (VEGF-C) and density of lymphatic vessel density was evaluated in tumor tissues. TUNEL assay was done for apoptosis. The outcomes of study revealed that TPX and ERB alone inhibited the growth of tumor but their combination showed a synergistic antitumor activity. TPX and ERB alone resulted in apoptosis and antiproliferative effect, whereas their combination showed highly significant results (P<0.01). TPX alone and its combination with ERB suppressed 5-LOX, COX-2, EGFR and VEGF-C and caused inhibition of lymphangiogenesis, however ERB alone was unable to affect expression of VEGF-C and lymphangiogenesis. The results confirmed combination of TPX and ERB produced a synergistic anticancer and antitumor activity, possibly by promoting apoptosis and antiproliferative effect on tumor cells via suppressing expression of COX-2, 5-LOX, EGFR and VEGF-C.