Antitumor activity of a novel oncrasin analogue is mediated by JNK activation and STAT3 inhibition.

Abstract

BACKGROUND:

To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1.

METHODOLOGY AND PRINCIPAL FINDINGS:

In vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI(50)) for eight of the most sensitive cell lines was ≤ 10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity.

CONCLUSIONS:

NSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors.

• Authors: Wei Guo, Shuhong Wu, Li Wang, Xiaoli Wei, Xiaoying Liu, Ji Wang, Zhimin Lu, Melinda Hollingshead, Bingliang Fang
• Journal: PloS one (PLoS One) Vol. 6 Issue 12 Pg. e28487 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22174819 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-((3-chlorophenyl)methyl)-1H-indole-3-carbinol
• Antineoplastic Agents
• Indoles
• Protein Kinase Inhibitors
• STAT3 Transcription Factor
• oncrasin-1
• JNK Mitogen-Activated Protein Kinases
• RNA Polymerase II

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Enzyme Activation (drug effects)
• Female
• Humans
• Indoles (chemistry, pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Mice
• Mice, Nude
• Protein Kinase Inhibitors (pharmacology)
• RNA Polymerase II (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Subcutaneous Tissue (drug effects, pathology)
• Xenograft Model Antitumor Assays