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 G(1) 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 G(1) accumulation induced by
exisulind, increased the fraction of cells in G(2)-M (9-17%), and increased apoptosis (5-62%). The IC(50) for in vitro growth inhibition by
exisulind alone was approximately 200 microM 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.