MT103 inhibits tumor growth with minimal toxicity in murine model of lung carcinoma via induction of apoptosis.
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 topology-based 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.
Jasinski
Piotr
P
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Zwolak
Pawel
P
Isaksson Vogel
Rachel
R
Bodempudi
Vidya
V
Terai
Kaoru
K
Galvez
Jorge
J
Land
David
D
Dudek
Arkadiusz Z
AZ
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001892:Camphanes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000648:ultrastructure; D008207:Lymphatic Metastasis / Q000473:pathology; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D016019:Survival Analysis; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D001892:Camphanes; C568788:N,N-dicyclohexyl-isoborneol-10-sulfonamide; D013449:Sulfonamides; D011493:Protein Kinase C; C022871:isoborneol
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