PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms
Copyright policy )PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms
PRIMA-1met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1met is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1met induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1met mediated activity. In human xenograft model of disease, PRIMA-1met effectively suppresses CRC tumor growth. Our results uncover distinct mechanisms of PRIMA-1met in CRC with different p53 status, thus providing a mechanistic rationale to evaluate the clinical efficacy of PRIMA-1met in CRC patients with different p53 status.
- National University Hospital Singapore
- National University of Singapore Singapore
- Department of Medicine Italy
- National University of Singapore Libraries Singapore
- Nationl University of Singapore Singapore
Quinuclidines, cell migration, protein p53, cancer inhibition, Mice, SCID, Mice, Mice, Inbred NOD, dose response, animal, genetics, antineoplastic agent, HT-29 cell line, TP53 protein, apoptosis, unclassified drug, PUMA protein, female, Colorectal Neoplasms, HT29 Cells, animal experiment, quinuclidine derivative, 610, colorectal cancer, colony formation, protein Noxa, Article, cancer growth, Caco-2 cell line, SCID mouse, Animals, Humans, controlled study, human, drug screening, prima 1 met, protein expression, mouse, Cell Proliferation, nonhuman, treatment duration, animal model, clinical effectiveness, human cell, disease model, nonobese diabetic mouse, treatment response, Xenograft Model Antitumor Assays, Disease Models, Animal, cell proliferation, 2-hydroxymethyl-2-methoxymethylazabicyclo(2.2.2)octan-3-one, drug effects, Disease Models, pathology, Caco-2 Cells, Tumor Suppressor Protein p53, metabolism, upregulation
Quinuclidines, cell migration, protein p53, cancer inhibition, Mice, SCID, Mice, Mice, Inbred NOD, dose response, animal, genetics, antineoplastic agent, HT-29 cell line, TP53 protein, apoptosis, unclassified drug, PUMA protein, female, Colorectal Neoplasms, HT29 Cells, animal experiment, quinuclidine derivative, 610, colorectal cancer, colony formation, protein Noxa, Article, cancer growth, Caco-2 cell line, SCID mouse, Animals, Humans, controlled study, human, drug screening, prima 1 met, protein expression, mouse, Cell Proliferation, nonhuman, treatment duration, animal model, clinical effectiveness, human cell, disease model, nonobese diabetic mouse, treatment response, Xenograft Model Antitumor Assays, Disease Models, Animal, cell proliferation, 2-hydroxymethyl-2-methoxymethylazabicyclo(2.2.2)octan-3-one, drug effects, Disease Models, pathology, Caco-2 Cells, Tumor Suppressor Protein p53, metabolism, upregulation
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