Disease relevance of NSC658402

• Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells [1].
• Arotinoid mofarotene (RO40-8757) up-regulates p21 and p27 during growth inhibition of pancreatic cancer cell lines [2].
• To understand the mechanism of action of the antitumor arotinoid mofarotene (Ro 40-8757), differential screening of cDNA libraries with cDNA probes prepared from treated or untreated breast-cancer cells was performed [3].
• A marked increase in the fraction of cells in G1 phase of the cell cycle was observed after mofarotene treatment; this was associated with marked up-regulation of p21/p27 and a shift of retinoblastoma protein into the hypophosphorylated form [2].
• Although 10 microM mofarotene did not reduce the translocative movements of melanoma cells, it significantly inhibited stationary motility, including fast plasma membrane movements and changes in shape [4].

High impact information on NSC658402

• The effect of the arotinoid mofarotene (Ro 40-8757; 4-[2-[p-[(E)- 2(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)- propenyl]phenoxy]ethyl]morpholine) on stromal cell-mediated hematopoiesis was examined in murine long-term bone marrow cultures [5].
• However, after mofarotene treatment ceased, progenitor cell levels began increasing immediately, and cell production reached plateau levels comparable with those of control cultures within 4 weeks [5].
• Mofarotene (Ro 40-8757) inhibits hematopoiesis in vitro by preventing maturation from primitive progenitor cells [5].
• Mofarotene did not inhibit colony formation by bone marrow cells stimulated by exogenous growth factors and did not decrease production of growth factors by stromal cells in the cultures, as determined by functional assays and by mRNA levels [5].
• In the search for retinoids active against Burkitt's lymphoma (BL), we found that the arotinoid mofarotene (Ro 40-8757) induced strong antiproliferative and apoptotic responses in most established BL cell lines as well as in primary BL cells [1].

Chemical compound and disease context of NSC658402

• In conclusion, our data demonstrate that mofarotene, an already almost forgotten synthetic retinoid, shows interesting effects on melanoma cells, which may be relevant for a slowdown of tumour spread [4].

Biological context of NSC658402

• These results indicate that down-regulation of mitochondrial gene transcription is specific to mofarotene and may explain, in part, the anti-proliferative effects of this compound [3].
• In conclusion, mofarotene inhibits the growth of pancreatic cancer cells by inducing G1-phase cell cycle-inhibitory factors (p21, p27 and hypophosphorylated form of Rb protein) and is considered to be a useful agent for pancreatic cancer treatment [2].
• Mofarotene showed half-maximal inhibition of cell proliferation at concentrations between 0.14 x 10(-6) and 3.8 x 10(-6) mol/l with little cytotoxicity [2].
• However, rat and dog were also confirmed to be suitable species for assessing the safety of mofarotene, and were used in toxicology [6].
• Metabolism of mofarotene in hepatocytes and liver microsomes from different species. Comparison with in vivo data and evaluation of the cytochrome P450 isoenzymes involved in human biotransformation [6].

Anatomical context of NSC658402

• The involvement of cytochrome P450 (CYP) in the metabolism of mofarotene was examined with human liver microsomes [6].
• Mofarotene also showed a pronounced effect on the organization of vinculin-containing cell-substratum adhesion plaques [4].

Associations of NSC658402 with other chemical compounds

• The retinoids, all-trans and 9-cis retinoic acids, did not affect the expression of NDI in MDA-MB-231 cells, demonstrating that mofarotene was not acting through the nuclear retinoic-acid receptors [3].

Gene context of NSC658402

• Repeated administration of mofarotene had no effect on CYP2E1 [6].
• Finally, the potential induction by mofarotene of four major CYP isoenzymes was investigated in rats [6].
• Several genes were identified that appeared to be regulated by mofarotene, including a mitochondrial gene encoding a subunit of NADH dehydrogenase (NDI) [3].
• Two mitochondrial proteins encoded in the nucleus, ATPase beta subunit and mitochondrial transcription factor I, were not down-regulated by mofarotene [3].
• Mofarotene-induced inhibition of melanoma cell motility by increasing vinculin-containing focal contacts [4].

Analytical, diagnostic and therapeutic context of NSC658402

• The pharmacokinetics of mofarotene were investigated in mice, rats and dogs following single intravenous and oral administrations [7].

References