ARC (NSC 188491) has identical activity to Sangivamycin (NSC 65346) including inhibition of both P-TEFb and PKC.
BACKGROUND
The nucleoside analog, ARC (NSC 188491) is a recently characterized transcriptional inhibitor that selectively kills cancer cells and has the ability to perturb angiogenesis in vitro. In this study, the mechanism of action of ARC was further investigated by comparing in vitro and in vivo activity with other anti-neoplastic purines.


METHODS
Structure-based homology searches were used to identify those compounds with similarity to ARC. Comparator compounds were then evaluated alongside ARC in the context of viability, cell cycle and apoptosis assays to establish any similarities. Following this, biological overlap was explored in detail using gene-expression analysis and kinase inhibition assays.


RESULTS
Results demonstrated that sangivamycin, an extensively characterized pro-apoptotic nucleoside isolated from Streptomyces, had identical activity to ARC in terms of 1) cytotoxicity assays, 2) ability to induce a G2/M block, 3) inhibitory effects on RNA/DNA/protein synthesis, 4) transcriptomic response to treatment, 5) inhibition of protein kinase C, 6) inhibition of positive transcription elongation factor b (P-TEFb), 7) inhibition of VEGF secretion, and 8) activity within hollow fiber assays. Extending ARC activity to PKC inhibition provides a molecular basis for ARC cancer selectivity and anti-angiogenic effects. Furthermore, functional overlap between ARC and sangivamycin suggests that development of ARC may benefit from a retrospective of previous sangivamycin clinical trials. However, ARC was found to be inactive in several xenograft models, likely a consequence of rapid serum clearance.


CONCLUSIONS
Overall, these data expand on the biological properties of ARC but suggest additional studies are required before it can be considered a clinical trials candidate.
Stockwin
Luke H
LH
Developmental Therapeutics Program, SAIC-Frederick Inc, NCI- Frederick, Frederick, MD 21702, USA. Stockwin@ncifcrf.gov
Yu
Sherry X
SX
Stotler
Howard
H
Hollingshead
Melinda G
MG
Newton
Dianne L
DL
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
C509961:4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009705:Nucleosides; D047428:Protein Kinase Inhibitors; D011741:Pyrimidine Nucleosides; D011743:Pyrimidines; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; C005699:sangivamycin; D042925:Positive Transcriptional Elongation Factor B; D011493:Protein Kinase C; D012319:RNA Polymerase II