P53 INDEPENDENT G(0) G(1) ARREST AND APOPTOSIS INDUCED BY A NOVEL RETINOID IN HUMAN BREAST-CANCER CELLS/

The biological activity of a novel synthetic retinoid 6-[3-(1-adamanty l)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) was investiga ted in human breast carcinoma (HBC) cells. Although capable of selecti ve binding to the RAR gamma nuclear receptor, AHPN inhibited the growt h of a number of HBC cell lines via RAR- or RXR-independent pathways. AHPN also inhibited the growth of the human leukemia cell line HL-60R which does not possess functional RARs. RA significantly inhibited AP- 1 mediated gene activation in MCF-7 cells while AHPN displayed no such anti-AP-1 activity. Retinoids normally are cytostatic in their inhibi tion of breast carcinoma growth and permit cell proliferation upon the ir removal, whereas AHPN induced G(0)/G(1) arrest within 6 h followed by apoptosis. In MCF-7 cells that harbor wild type p53, AHPN-induced G (0)/G(1) arrest and apoptosis was accompanied by p53-independent regul ation of WAF1/CIP1 as well as bar mRNA levels while bcl-2 mRNA levels were decreased. In MDA-MB-231 cells which possess a mutant p53, AHPN-m ediated G(0)/G(1) arrest and apoptosis was also associated with a conc omitant up regulation of WAF1/CIP1 mRNA while these cells did not expr ess bar or bcl-2 messages. Thus, AHPN represents a novel retinoid that induces G(0)/G(1) arrest and apoptosis via a unique pathway which app ears to involve activation of known downstream effecters of p53 in a p 53-independent manner.