Abstract
BackgroundTo 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 (GI50) 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.ConclusionsNSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors.
Highlights
Synthetic lethality screening has recently been used by various investigators to identify genes that are crucial for survival of certain oncogene-transformed cells [1,2] or that sensitize cells to chemotherapy [3], or small molecules that selectively induce cell death in a subset of oncogene-transformed cells [4,5,6]
If a cell line contains a mutation in one oncogene, synthetic lethality can be elicited by a small molecule that induces or mimics biological functions of a synthetic lethal mutation in the second gene
To optimize the compound we identified through synthetic lethality screening, we evaluated several analogues with chemical structures similar to that of oncrasin-1
Summary
Synthetic lethality screening has recently been used by various investigators to identify genes that are crucial for survival of certain oncogene-transformed cells [1,2] or that sensitize cells to chemotherapy [3], or small molecules that selectively induce cell death in a subset of oncogene-transformed cells [4,5,6]. If a cell line contains a mutation in one oncogene, synthetic lethality can be elicited by a small molecule that induces or mimics biological functions of a synthetic lethal mutation in the second gene. NSC-741909 (1-[(4-chlorophenyl) methyl]-1H-indole-3methanol, oncrasin-60), was found to suppress the growth of several NCI-60 cancer cell lines with a unique anticancer spectrum [7]. 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. We investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3methanol, oncrasin-72), one of most potent analogues of oncrasin-1
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