Arsenic sulfide combined with JQ1, chemotherapy agents, or celecoxib inhibit gastric and colon cancer cell growth

BACKGROUND: Arsenic compounds have modest cytotoxic activity in solid tumors. We investigated if arsenic sulfide (As(4)S(4)) in combination with other distinct agents could enhance its cytotoxic activity. METHODS: We used gastric and colon cancer cell lines to study the synergistic effect of As(4)S(4) in combination with BRD4 inhibitor JQ1, or with chemotherapy drug cisplatin and irinotecan or with COX2 inhibitor celecoxib. We investigated the mechanism of the cytotoxic effect of these novel combinations. RESULTS: We found that when As(4)S(4) was combined with JQ1, cisplatin, irinotecan or celecoxib, its cytotoxic activity was dramatically enhanced in both gastric and colon cancer cell lines. As(4)S(4) and JQ1 inhibited BRD4 and c-Myc while activating p53 expression synergistically. As(4)S(4) inhibited COX2 and cyclin D1 expression. When As(4)S(4) was combined with chemotherapy drug cisplatin or COX2 inhibitor celecoxib, its inhibition of COX2, BCL2, and p38 expression was enhanced. As(4)S(4) and cisplatin synergistically stimulated p53, phosphor-p38 (p-p38), and increased cleaved caspase 3 (c-caspase 3). CONCLUSION: As(4)S(4) in combination with JQ1, cisplatin, irinotecan or celecoxib showed enhanced cytotoxic effect on gastric and colon cancer cells, indicating the potential application of these novel drug combinations as part of treatment strategy that warrants further investigation. As(4)S(4) and JQ1 demonstrate synergistic activation of p53 and inhibition of c-Myc. As(4)S(4) and cisplatin and celecoxib activated multiple apoptosis pathways.