Additive inhibitory effects of retinoids and interferon-alpha on the growth of human cervical carcinoma cells

The combination of 13-cis retinoic acid (13CRA) and interferon-alpha (IFN-alpha) has shown marked antitumor activity against locally advanced cervical cancer in vivo. To begin to explore the mechanism and potential of the efficacy of this combination, the sensitivity of 9 cervical carcinoma cell lines to the growth inhibitory effects of these agents was examined after 1 to 7 days of treatment. IFN-alpha (100 U/ml) alone exerted variable effects. SiHa cell line was very sensitive showing 75% inhibition. ME180, CaSki, MS751, and C33-A cell lines were moderately inhibited (30-45% inhibition), and C41, HeLa, and HT-3 cell lines were poorly responsive (20% inhibition or less). 13CRA (10(-9) to 10(-6) M) alone also caused variable growth inhibitory effect. ME180, SiHa, and HT-3 exhibited considerable inhibition (IC(50)s of 9x10(-8), 4x10(-8), and 7x10(-8) M, respectively and maximal inhibition of 80%, 79%, and 83% at 10(-6) M) and the other cell lines showed minor responses (20-45% inhibition at 10(-6) M). ME180, MS751, C41, and HeLa demonstrated additive growth inhibitory effects of 13CRA and IFN-alpha whereas the other 4 cell lines showed no additive effects. All the cell lines expressed mRNAs for the nuclear retinoid receptors (RARs and RXRs) RAR-alpha, RAR-gamma, and RXR-alpha, however, RAR-beta mRNA was detected only in ME180, MS751, C4I, and CaSki. Treatment with retinoic acid increased RAR-alpha level in C4I, HT-3, and CaSki; RAR-beta in HT-3; and RAR-gamma in HT-3 and C4I cells. IFN-alpha treatment did not exert any effect on the level of mRNA for any of the retinoid receptors in any of the cell lines or on the level of HPV18 E6 and E7 mRNA in HeLa cells. Treatment with the combination of RA and IFN-alpha did not affect the level of receptor mRNAs differently than RA alone did. There appeared to be no correlation between the responses of the cells to these agents and the presence or type of nuclear retinoid receptor, human papillomavirus, or mutant p53 in the cells.