MT103 inhibits tumor growth with minimal toxicity in murine model of lung carcinoma via induction of apoptosis

Piotr Jasinski, Pawel Zwolak, Rachel Isaksson Vogel, Vidya Bodempudi, Kaoru Terai, Jorge Galvez, David Land, Arkadiusz Z. Dudek

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Molecular topology (MT) was used to develop quantitative structure-activity relationship (QSAR) models to screen databases for new anticancer compounds. One of the selected compounds was MT103, an isoborneol derivative, with a promising profile predicted to slow tumor growth through pro-apoptotic signaling and protein kinase C inhibition. We found that MT103 inhibited the growth of a wide variety of cancer cell types as verified by the NCI-60 cancer cell line panel. MTT cell viability assay showed that MT103 inhibited 50% of the growth of HOP-92, ACHN, NCI-H226, MCF-7, and A549 cancer cell lines at much lower concentrations than that required for HUVECs and human fibroblasts. MT103 stimulated apoptosis in NCI-H226 lung carcinoma cells as measured by oligonucleosomal DNA fragmentation. However, protein kinase C was not targeted by MT103, as predicted by in silico modeling. MT103 slowed in vivo tumor growth and metastatic spread of NCI-H226 cells injected subcutaneously into NOD/SCID mice, without eliciting any severe adverse events as monitored by animal survival, blood serum analysis, and histological analysis of organs. Oral administration of MT103 nanoparticles (200 nm in diameter), which were generated with ElectroNanospray technology, inhibited in vivo growth of HOP-92 lung carcinoma cells almost as effectively as intraperitoneal injections of cisplatin. Taken together, our study of a novel anti-cancer drug identified using a molecular topologybased approach to drug discovery demonstrates that MT103 has anti-tumor activity in vitro and in vivo, although additional studies are needed to elucidate its mechanism of action.

Original languageEnglish (US)
Pages (from-to)846-852
Number of pages7
JournalInvestigational New Drugs
Volume29
Issue number5
DOIs
StatePublished - Oct 1 2011

Keywords

  • In vivo antitumor activity
  • In vivo toxicity
  • MT103
  • New drug development

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