Targeting of the Akt-nuclear factor-κB signaling network by [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), a novel indole-3-carbinol derivative, in a mouse model of hepatocellular carcinoma

Hany A. Omar, Aaron M. Sargeant, Jing Ru Weng, Dasheng Wang, Samuel K. Kulp, Tushar C Patel, Ching Shih Chen

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Constitutive activation of Akt and nuclear factor-κB (NF-κB) represents major cellular abnormalities associated with the development and progression of hepatocellular carcinoma (HCC). Based on the structure of indole-3-carbinol, a chemopreventive phytochemical, we developed a novel derivative, [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), that exhibits higher potency in inducing apoptosis by targeting the Akt-NF-κB signaling network. This study was aimed at assessing the antitumor activity of OSU-A9 using both in vitro and in vivo models of HCC, a malignancy in which the Akt-NF-κB signaling network plays major roles in pathogenesis and therapeutic resistance. Our data show that OSU-A9 was 100 times more potent than indole-3-carbinol in suppressing the viability of Hep3B, Huh7, and PLC5 HCC cells with IC50 values ranging from 2.8 to 3.2 μM. OSU-A9 interfered with the interplay between Akt- and NF-κB-mediated oncogenic signaling, leading to changes in the functional status of diverse signaling effectors involved in cell cycle progression, apoptosis, angiogenesis, and metastasis. The in vivo efficacy of OSU-A9 was assessed in nude mice bearing luciferase-expressing Hep3B xenograft tumors. Daily oral treatments with OSU-A9 at 25 or 50 mg/kg for 56 days suppressed tumor growth by 67 and 80%, respectively, which was correlated with changes in intratumoral biomarkers pertinent to Akt-NF-κB signaling, and without apparent toxicity or evidence of hepatic biotransformation enzyme induction. Together, these findings indicate that OSU-A9 is a potent, orally bioavailable inhibitor of the Akt-NF-κB signaling network with a broad spectrum of antitumor activity that includes targets regulating multiple aspects of HCC pathogenesis and progression.

Original languageEnglish (US)
Pages (from-to)957-968
Number of pages12
JournalMolecular Pharmacology
Volume76
Issue number5
DOIs
StatePublished - Nov 2009
Externally publishedYes

Fingerprint

Methanol
Hepatocellular Carcinoma
Apoptosis
Neoplasms
Enzyme Induction
Phytochemicals
Biotransformation
Luciferases
Heterografts
Nude Mice
Inhibitory Concentration 50
Cell Cycle
Biomarkers
Neoplasm Metastasis
indole-3-carbinol
Liver
Growth
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Targeting of the Akt-nuclear factor-κB signaling network by [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), a novel indole-3-carbinol derivative, in a mouse model of hepatocellular carcinoma. / Omar, Hany A.; Sargeant, Aaron M.; Weng, Jing Ru; Wang, Dasheng; Kulp, Samuel K.; Patel, Tushar C; Chen, Ching Shih.

In: Molecular Pharmacology, Vol. 76, No. 5, 11.2009, p. 957-968.

Research output: Contribution to journalArticle

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abstract = "Constitutive activation of Akt and nuclear factor-κB (NF-κB) represents major cellular abnormalities associated with the development and progression of hepatocellular carcinoma (HCC). Based on the structure of indole-3-carbinol, a chemopreventive phytochemical, we developed a novel derivative, [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), that exhibits higher potency in inducing apoptosis by targeting the Akt-NF-κB signaling network. This study was aimed at assessing the antitumor activity of OSU-A9 using both in vitro and in vivo models of HCC, a malignancy in which the Akt-NF-κB signaling network plays major roles in pathogenesis and therapeutic resistance. Our data show that OSU-A9 was 100 times more potent than indole-3-carbinol in suppressing the viability of Hep3B, Huh7, and PLC5 HCC cells with IC50 values ranging from 2.8 to 3.2 μM. OSU-A9 interfered with the interplay between Akt- and NF-κB-mediated oncogenic signaling, leading to changes in the functional status of diverse signaling effectors involved in cell cycle progression, apoptosis, angiogenesis, and metastasis. The in vivo efficacy of OSU-A9 was assessed in nude mice bearing luciferase-expressing Hep3B xenograft tumors. Daily oral treatments with OSU-A9 at 25 or 50 mg/kg for 56 days suppressed tumor growth by 67 and 80{\%}, respectively, which was correlated with changes in intratumoral biomarkers pertinent to Akt-NF-κB signaling, and without apparent toxicity or evidence of hepatic biotransformation enzyme induction. Together, these findings indicate that OSU-A9 is a potent, orally bioavailable inhibitor of the Akt-NF-κB signaling network with a broad spectrum of antitumor activity that includes targets regulating multiple aspects of HCC pathogenesis and progression.",
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