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ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells.
Narayan, Satya; Ramisetti, Srinivasa; Jaiswal, Aruna S; Law, Brian K; Singh-Pillay, Ashona; Singh, Parvesh; Amin, Shantu; Sharma, Arun K.
Afiliação
  • Narayan S; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, 32610, USA. Electronic address: snarayan@ufl.edu.
  • Ramisetti S; Department of Pharmacology, Penn State University College of Medicine, Penn State Cancer Institute, Hershey, PA, 17033, USA.
  • Jaiswal AS; Department of Hematology and Oncology, University of Florida, Gainesville, FL, 32610, USA.
  • Law BK; Department of Pharmacology and Experimental Therapeutics, University of Florida, Gainesville, FL, 32610, USA.
  • Singh-Pillay A; School of Chemistry and Physics, University of Kwa-Zulu Natal (UKZN), Westville Campus, Durban, 4000, South Africa.
  • Singh P; School of Chemistry and Physics, University of Kwa-Zulu Natal (UKZN), Westville Campus, Durban, 4000, South Africa.
  • Amin S; Department of Pharmacology, Penn State University College of Medicine, Penn State Cancer Institute, Hershey, PA, 17033, USA.
  • Sharma AK; Department of Pharmacology, Penn State University College of Medicine, Penn State Cancer Institute, Hershey, PA, 17033, USA. Electronic address: asharma1@pennstatehealth.psu.edu.
Eur J Med Chem ; 161: 456-467, 2019 Jan 01.
Article em En | MEDLINE | ID: mdl-30384048
Despite new agent development and short-term benefits in patients with colorectal cancer (CRC), metastatic CRC cure rates have not improved due to high rates of 5-fluorouracil (5-FU)/leucovorin/oxaliplatin (FOLFOX)-resistance and a clinical therapeutic plateau. At the same time, this treatment regime leads to significant toxicity, cost, and patient inconvenience. Drug-resistance is linked to CRC stem cells, which are associated with the epidermal-to-mesenchymal transition (EMT) pathway. Thus, to optimally treat CRC, a therapy that can target the cell survival and EMT pathways in both CRC bulk and stem cell populations is critical. We recently identified a novel small molecule NSC30049 (7a) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC bulk, FOLFOX-resistant, and CRC stem cells both in vitro and in vivo models. In the present study, we report the synthesis and anti-CRC evaluation of several stable and effective 7a analogs. ASR352 (7b) was identified as one of the equipotent 7a analogs that inhibited the growth of CRC bulk cells, sensitized FOLFOX-resistant cells, and reduced the sphere formation capacity of CRC stem cells. It appears that the complex mechanism of cytotoxicity for 7b includes abrogation of 5-FU-induced the S phase, reduction of the phosphorylation of Chk1 at S317P, S345P and S296P, increased γH2AX staining, activation of caspase 3/PARP1 cleavage, and enhancement of Bax/Bcl2 ratio. Further 7b-mediated reduced phosphorylation of Chk1 was an indirect effect, since it did not inhibit Chk1 activity in an in vitro kinase assay. Our findings suggest that 7b as a single agent, or in combination with 5-FU can be developed as a therapeutic agent in CRC bulk, FOLFOX-resistant, and CRC stem cell populations for unmanageable metastatic CRC conditions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco / Compostos Aza / Adamantano / Neoplasias Colorretais / Resistencia a Medicamentos Antineoplásicos / Fluoruracila / Oxaliplatina / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Eur J Med Chem Ano de publicação: 2019 Tipo de documento: Article País de publicação: França

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco / Compostos Aza / Adamantano / Neoplasias Colorretais / Resistencia a Medicamentos Antineoplásicos / Fluoruracila / Oxaliplatina / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Eur J Med Chem Ano de publicação: 2019 Tipo de documento: Article País de publicação: França