Is growth inhibition and induction of apoptosis in lung cancer cell lines by fenretinide [N-(4-hydroxyphenyl)retinamide] sufficient for cancer therapy?

The synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide, 4-HPR] has demonstrated growth inhibition and induction of apoptosis of various malignant cells, including lung cancer cell lines. 4-HPR is now being investigated in several clinical trials. In our study, we show that 4-HPR inhibits growth on a broad panel of lung cancer cell lines (12/12 small cell lung cancer and 9/12 nonsmall cell lung cancer cell lines), including cell lines unresponsive to all-trans-retinoic acid (ATRA). 4-HPR revealed a higher potency than ATRA in inhibiting cell growth with IC(50) values ranging from 3.3-8.5 microM. Furthermore, 4-HPR induces apoptosis in lung cancer cell lines as proven by TUNEL and annexin V assay. Despite this, we observed stimulation of growth in 2 SCLC cell lines at 1 microM 4-HPR. In advance to the clinical application of 4-HPR, we demonstrate that growth inhibition is reversible after removal of 4-HPR and that long-term application is necessary. Through long-term stimulation with 4-HPR, we cultivated 3 resistant cell lines that were still inhibited by 4-HPR after several weeks, however, exhibited almost no apoptosis. These cell lines exhibited morphologic changes, which in the case of the SCLC cell lines suggested differentiation. Our data show that 4-HPR inhibits growth in lung cancer cell lines by varying mechanisms including (i) cytostasis, (ii) apoptosis and (iii) presumably, differentiation. In contrast, the observed growth stimulation, reversibility of growth inhibition and development of resistance to apoptosis make successful cancer therapy uncertain and may limit clinical application of 4-HPR in lung cancer patients, although its inhibitory effects last over several weeks.