Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell line

Non-small cell lung cancer (NSCLC) cells have constitutively high expressio n of cytosolic phospholipase A2 (cPLA(2)) and cyclooxygenase (COX) 2, These NSCLC cells also have increased prostaglandin expression (PGE(2)). Many lu ng cancers also express 12-lipoxygenase RNA and 12-lipoxygenase protein and biosynthesize 12(S)-hydroxyeicosatetraenoic acid, which correlates with th eir metastatic potential, Several studies have demonstrated that COX-1 and COX-2 inhibitors could inhibit the in vitro growth of human lung cancer cel l lines, In this report, we evaluated the growth-inhibitory effects of suli ndac sulfide, a COX-1 and COX-2 inhibitor; exisulind (sulindac sulfone), a novel proapoptotic agent that does not inhibit COX enzymes; and nordihydrog uaiaretic acid (NDGA), a lipoxygenase inhibitor on human lung cancer cell l ines, We compared these effects with those of 13-cis-retinoic acid, a chemo prevention agent, and with the cytotoxic chemotherapeutic agents paclitaxel and cisplatin, alone or in combination. Our goal was to develop new chemop revention and treatment strategies, Each of the six agents tested inhibited the in vitro growth of three NSCLC and three SCLC cell lines at the highes t concentration. Paclitaxel was the most patent agent (IC50 = 0.003-0.150 m u M); sulindac sulfide, NDGA, and 13-cis-retinoic acid had intermediate pot ency (IC50 = 4-80 mu M) and cisplatin and exisulind were the least potent ( IC50 = 150-600 mu M). Combination studies showed synergistic interactions f or sulindac sulfide, exisulind, and NDGA with paclitaxel, cisplatin, and 13 -cis-retinoic acid, regardless of drug-resistance phenotype. At high concen trations, the combination of 13-cis-retinoic acid and each of the five othe r drugs resulted in a strong synergistic effect. These studies provide a ra tionale for chemoprevention (exisulind +/- retinoic acid +/- NDGA) and ther apeutic (exisulind +/- paclitaxel +/- cisplatin) studies in patients at ris k for, or with, lung cancer.