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Homospisulosine induced apoptosis in cervical carcinoma cells is associated with phosphorylation of Bcl-2 and up-regulation of p27/Kip1

MB. Pilatova, N. Nosalova, G. Ockajakova, M. Kello, K. Kotorova, P. Takac, P. Petik, P. Bohus, K. Stankova, M. Martinkova, R. Mezencev

. 2023 ; 21 (4) : 218-227. [pub] 20231128

Jazyk angličtina Země Česko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24002961

Grantová podpora
1/0278/23 Slovak Grant Agency for Science VEGA No - Slovakia
1/0539/21 Slovak Grant Agency for Science VEGA No - Slovakia
1/0653/19 Slovak Grant Agency for Science VEGA No - Slovakia
ITMS2014 Operational Programme Integrated Infrastructure - Slovakia
313011V455 Operational Programme Integrated Infrastructure - Slovakia

Spisulosine (1-deoxysphinganine) is a sphingoid amino alcohol isolated from the sea clams that showed potent antiproliferative activity against a broad spectrum of solid tumors but failed in clinical trials due to neurotoxicity. However, its structural similarity to other bioactive sphingoids, interesting mode of action, and appreciable potency against cancer cells make it a suitable lead for future anticancer drug development. The present study was conducted to elucidate mechanisms of the antiproliferative/cytotoxic effects of newly synthesized spisulosine analog homospisulosine (KP7). The evaluation was performed on cervical carcinoma cells, representing an in vitro model of one of the most common cancer types and a significant worldwide cause of women's cancer mortality. Treatment with homospisulosine (2.0 μM) for 24, 48, and 72 h significantly inhibited the growth of HeLa cells in vitro and induced apoptosis detectable by DNA fragmentation, externalization of phosphatidylserine, dissipation of mitochondrial membrane potential, activation of caspase-3 and cleavage of PARP. In addition, treating HeLa cells with spisulosine increased p27 and Bcl-2 on protein levels and phosphorylation of Bcl-2 on Ser70 residue. These results support the potential for spisulosine analogs represented here by homospisulosine for future therapeutic development.

Citace poskytuje Crossref.org

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$a Spisulosine (1-deoxysphinganine) is a sphingoid amino alcohol isolated from the sea clams that showed potent antiproliferative activity against a broad spectrum of solid tumors but failed in clinical trials due to neurotoxicity. However, its structural similarity to other bioactive sphingoids, interesting mode of action, and appreciable potency against cancer cells make it a suitable lead for future anticancer drug development. The present study was conducted to elucidate mechanisms of the antiproliferative/cytotoxic effects of newly synthesized spisulosine analog homospisulosine (KP7). The evaluation was performed on cervical carcinoma cells, representing an in vitro model of one of the most common cancer types and a significant worldwide cause of women's cancer mortality. Treatment with homospisulosine (2.0 μM) for 24, 48, and 72 h significantly inhibited the growth of HeLa cells in vitro and induced apoptosis detectable by DNA fragmentation, externalization of phosphatidylserine, dissipation of mitochondrial membrane potential, activation of caspase-3 and cleavage of PARP. In addition, treating HeLa cells with spisulosine increased p27 and Bcl-2 on protein levels and phosphorylation of Bcl-2 on Ser70 residue. These results support the potential for spisulosine analogs represented here by homospisulosine for future therapeutic development.
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