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

• Published in: Cancer research (Chicago, Ill.) Vol. 59; no. 24; pp. 6178 - 6184
• Main Authors: SORIANO, A. F, HELFRICH, B, CHAN, D. C, HEASLEY, L. E, BUNN, P. A, CHOU, T.-C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-12-1999
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - prevention & control; Cell Cycle - drug effects; Cell Survival - drug effects; Chemoprevention; Chemotherapy; Cyclooxygenase Inhibitors - pharmacology; Drug Synergism; Humans; Lipoxygenase Inhibitors - pharmacology; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Medical sciences; Pharmacology. Drug treatments; Tumor Cells, Cultured; Prostaglandin-endoperoxide synthase; Retinoid; Cytotoxicity; Arachidonic acid; Bronchopulmonary; Prevention; Sulindac; Taxane derivatives; Cell cycle; Established cell line; Paclitaxel; Bronchus disease; Indene derivatives; Drug interaction; Mechanism of action; Small cell carcinoma; Tumor cell; Non small cell carcinoma; Platinum II Complexes; Human; Lung disease; Drug combination; Respiratory disease; Enzyme; Enzyme inhibitor; Malignant tumor; Acetic acid derivative; In vitro; Cisplatin; Non steroidal antiinflammatory agent; Chemotherapy; Treatment; Isotretinoin; Oxidoreductases; Lipoxygenase; Apoptosis
• ISSN: 0008-5472; 1538-7445

Non-small cell lung cancer (NSCLC) cells have constitutively high expression of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase (COX) 2. These NSCLC cells also have increased prostaglandin expression (PGE2). Many lung cancers also express 12-lipoxygenase RNA and 12-lipoxygenase protein and biosynthesize 12(S)-hydroxyeicosatetraenoic acid, which correlates with their metastatic potential. Several studies have demonstrated that COX-1 and COX-2 inhibitors could inhibit the in vitro growth of human lung cancer cell lines. In this report, we evaluated the growth-inhibitory effects of sulindac sulfide, a COX-1 and COX-2 inhibitor; exisulind (sulindac sulfone), a novel proapoptotic agent that does not inhibit COX enzymes; and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor on human lung cancer cell lines. We compared these effects with those of 13-cis-retinoic acid, a chemoprevention agent, and with the cytotoxic chemotherapeutic agents paclitaxel and cisplatin, alone or in combination. Our goal was to develop new chemoprevention and treatment strategies. Each of the six agents tested inhibited the in vitro growth of three NSCLC and three SCLC cell lines at the highest concentration. Paclitaxel was the most potent agent (IC50 = 0.003-0.150 microM); sulindac sulfide, NDGA, and 13-cis-retinoic acid had intermediate potency (IC50 = 4-80 microM), and cisplatin and exisulind were the least potent (IC50 = 150-500 microM). Combination studies showed synergistic interactions for sulindac sulfide, exisulind, and NDGA with paclitaxel, cisplatin, and 13-cis-retinoic acid, regardless of drug-resistance phenotype. At high concentrations, the combination of 13-cis-retinoic acid and each of the five other drugs resulted in a strong synergistic effect. These studies provide a rationale for chemoprevention (exisulind +/- retinoic acid +/- NDGA) and therapeutic (exisulind +/- paclitaxel +/- cisplatin) studies in patients at risk for, or with, lung cancer.