Exisulind in Combination with Docetaxel Inhibits Growth and Metastasis of Human Lung Cancer and Prolongs Survival in Athymic Nude Rats with Orthotopic Lung Tumors

Abstract

Docetaxel, a semisynthetic taxane, improves the survival of stage IIIB and IV non-small cell lung cancer patients. However, the 5-year survival remains poor, and few patients experience a complete remission. In this report, we evaluated the effects of exisulind, a novel proapoptotic agent that is a sulfone metabolite of sulindac, in combination with docetaxel on the growth of the human non-small cell lung cancer cell line A549 in vitro and in vivo. Exisulind is a novel sulindac metabolite in that it does not inhibit cyclooxygenase enzymes and has been shown to induce apoptosis in a variety of human cancers by inhibiting cyclic GMP-dependent phosphodiesterase. Exisulind alone increased the fraction of cells in the G₁ phase of the cell cycle from 46% to 65%, whereas it decreased the fraction of cells in the S phase from 38% to 14%. Docetaxel increased the fraction of cells in the S phase from 17% to 19%, and 10 nm docetaxel increased the G2-M phase by 23%. Docetaxel alone induced apoptosis from 11% to 64% at 12–24 h after incubation. The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution) reduced the G₁ accumulation induced by exisulind, increased the fraction of cells in G₂-M (9–17%), and increased apoptosis (5–62%). The IC₅₀ for in vitro growth inhibition by exisulind alone was ∼200 μm and 2.5 nm for docetaxel. The in vitro combination of exisulind and docetaxel produced an additive to synergistic growth inhibition. In athymic nude rats with A549 orthotopic lung cancers, both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases, and increased apoptosis compared with control animals treated with a carrier. However, the combination of exisulind with docetaxel significantly prolonged survival (P = < 0.0004), inhibited tumor growth and metastases (P = < 0.0001), and increased apoptosis (P = < 0.001) when compared with control animals. These results provide rationale for conducting clinical trials using the combination of exisulind and docetaxel in patients with advanced lung cancer.