Retinoic acid receptor beta expression and growth inhibition of gynecologic cancer cells by the synthetic retinoid N-(4-hydroxyphenyl) retinamide

J Natl Cancer Inst. 1998 Apr 15;90(8):597-605. doi: 10.1093/jnci/90.8.597.


Background: The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR) can inhibit the growth of tumor cells. Preliminary results from a clinical trial suggest that 4HPR may reduce ovarian cancer incidence. We examined the growth-inhibitory effects of 4HPR on gynecologic cancer cell lines in vitro and the role of retinoid receptors in modulating this effect.

Methods: Twelve human gynecologic cancer cell lines (the ovarian cell lines--A224, AD10, UCI 101, UCI 107, SKOV3, 222, CP70, ML3B, and ML5; the cervical cell lines--HT3 and ME180; and the endometrial cell line--Hec 1A were tested for sensitivity to 4HPR (by assaying cell proliferation rates). Gel electrophoretic analysis of DNA fragmentation was used to measure programmed cell death (apoptosis). Specific retinoid receptor (retinoic acid receptor [RAR] and retinoid X receptor) messenger RNA (mRNA) levels were measured by northern blot hybridization. AD10 cells were stably transfected with human RARbeta complementary DNA, and the effect of 4HPR on cell proliferation was examined.

Results: 4HPR inhibited the growth of all 12 cell lines, but to varying degrees; IC50 values (i.e., concentrations that inhibit proliferation by 50%) ranged from 0.3 to 9 microM. Following 4HPR treatment, ovarian cancer cells that were sensitive to 4HPR (222, CP70, and UCI 101; IC50 <3 microM) contained higher levels of RARbeta transcripts than more resistant cells (AD10, ME180, Hec 1A, and A224; IC50 > or =3 microM) (2.8-fold; two-sided P = .006). Anchorage-independent growth of transfected AD10 cells expressing high levels of RARbeta was totally abolished, even in the absence of 4HPR; transfectants expressing low levels of RARbeta exhibited lower levels of anchorage-independent growth and grew more slowly in the presence of 4HPR than control untransfected AD10 cells.

Conclusion: 4HPR inhibited the proliferation of ovarian cancer cells in vitro; RARbeta expression appeared to be associated with this effect.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Northern
  • Female
  • Fenretinide / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genital Neoplasms, Female / drug therapy*
  • Genital Neoplasms, Female / metabolism*
  • Humans
  • RNA, Messenger / analysis
  • RNA, Neoplasm / analysis
  • Receptors, Retinoic Acid / biosynthesis
  • Receptors, Retinoic Acid / drug effects*
  • Receptors, Retinoic Acid / genetics
  • Time Factors
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • Fenretinide