TY - JOUR
T1 - ASR352, A potent anticancer agent
T2 - Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells
AU - Narayan, Satya
AU - Ramisetti, Srinivasa
AU - Jaiswal, Aruna S.
AU - Law, Brian K.
AU - Singh-Pillay, Ashona
AU - Singh, Parvesh
AU - Amin, Shantu
AU - Sharma, Arun K.
N1 - Funding Information:
This work was supported partially by the Team Science Project #00110481, University of Florida Shands Cancer Center, Gainesville, FL to SN. AKS thanks the Department of Pharmacology, Penn State College of Medicine, and Penn State Cancer Institute (PSCI) for financial support. The authors thank Dr. Jyh-Ming Lin, Solution Phase NMR Facility at Core Research Facilities of the Penn State College of Medicine for recording NMR spectra, and Organic Synthesis Shared Resource of PSCI. The authors also thank the Centre for High Computing Performance (CHPC) based in Cape Town (South Africa) for access and use of computational resources.
Funding Information:
This work was supported partially by the Team Science Project # 00110481 , University of Florida Shands Cancer Center, Gainesville, FL to SN. AKS thanks the Department of Pharmacology, Penn State College of Medicine , and Penn State Cancer Institute (PSCI) for financial support. The authors thank Dr. Jyh-Ming Lin, Solution Phase NMR Facility at Core Research Facilities of the Penn State College of Medicine for recording NMR spectra, and Organic Synthesis Shared Resource of PSCI. The authors also thank the Centre for High Computing Performance (CHPC) based in Cape Town (South Africa) for access and use of computational resources.
Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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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U2 - 10.1016/j.ejmech.2018.10.052
DO - 10.1016/j.ejmech.2018.10.052
M3 - Article
C2 - 30384048
AN - SCOPUS:85055704248
VL - 161
SP - 456
EP - 467
JO - CHIM.THER.
JF - CHIM.THER.
SN - 0223-5234
ER -