1,1-Bis (3′-indolyl)-1-(p-substitutedphenyl)methane compounds inhibit lung cancer cell and tumor growth in a metastasis model

Terrick Andey, Apurva Patel, Tanise Jackson, Stephen Safe, Mandip Singh

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

1,1-Bis(3-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compounds exhibit remarkable antitumor activity with low toxicity in various cancer cells including lung tumors. Two C-DIM analogs, DIM-C-pPh-OCH3 (C-DIM-5) and DIM-C-pPhOH (C-DIM-8) while acting differentially on the orphan nuclear receptor, TR3/Nur77 inhibited cell cycle progression from G0/G1 to S-phase and induced apoptosis in A549 cells. Combinations of docetaxel (doc) with C-DIM-5 or C-DIM-8 showed synergistic anticancer activity in vitro and these results were consistent with their enhanced antitumor activities invivo. Respirable aqueous formulations of C-DIM-5 (mass median aerodynamic diameter of 1.92 ± 0.22 lm and geometric standard deviation of 2.31 ± 0.12) and C-DIM-8 (mass median aerodynamic diameter of 1.84 ± 0.31 lm and geometric standard deviation of 2.11 ± 0.15) were successfully delivered by inhalation to athymic nude mice bearing A549 cells as metastatic tumors. This resulted in significant (p < 0.05) lung tumor regression and an overall reduction in tumor burden. Analysis of lung tumors from mice treated with inhalational formulations of C-DIM-5 and C-DIM-8 showed decreased mRNA and protein expression of mediators of tumor initiation, metastasis, and angiogenesis including MMP2, MMP9, c-Myc, β-catenin, c-Met, c-Myc, and EGFR. Microvessel density assessment of lung tissue sections showed significant reduction (p < 0.05) in angiogenesis and metastasis as evidenced by decreased distribution of immunohistochemical staining of VEGF, and CD31. Our studies demonstrate both C-DIM-5 and C-DIM-8 have similar anticancer profiles in treating metastatic lung cancer and possibly work as TR3 inactivators.

Original languageEnglish (US)
Pages (from-to)227-241
Number of pages15
JournalEuropean Journal of Pharmaceutical Sciences
Volume50
Issue number2
DOIs
StatePublished - 2013

Keywords

  • Angiogenesis
  • Inhalation
  • Metastatic
  • Nebulizer
  • Nur77/TR3

ASJC Scopus subject areas

  • Pharmaceutical Science

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