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PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) induce apoptosis in K562 cells.
BMC Cancer. 2007 Nov 09; 7:207.BC

Abstract

BACKGROUND

The objective of this study was to gain insight into the molecular mechanism of induced cell death (apoptosis) by PYRROLO [1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) series compounds, using human (K562) cells as a model.

METHODS

We focused our attention on some members of the PBTDs family to test their potential apoptotic activity in K562 cells. Important apoptotic activity was demonstrated, as evidenced by the concentration and percentage of cell death quantified by measuring PI-uptake by flow cytometry, and DNA fragmentation analyzed by agarose gel electrophoresis, generating a characteristic ladder pattern of discontinuous DNA fragments. The expression of Bcl-2 family was tested using western blotting and transfection method.

RESULTS

PBTDs-mediated suppression of K562 cell proliferation was induced by apoptosis characterized by the appearance of DNA fragmentation and was associated with the poly(ADP-ribose)polymerase (PARP) cleavage. PBTD-1 and -3 treatment resulted in caspase-3 activation through down-regulation of Bcl-2 and up-regulation of Bax. Furthermore, we used K562/vector and K562/bcl-2 cells, which were generated by transfection of the cDNA of the Bcl-2 gene. As compared with K562/vector, K562/Bcl-2 cells exhibited a 4-fold greater expression of Bcl-2. Treatment with 10 muM PBTD-1 and -3 for 24 h produced morphological features of apoptosis and DNA fragmentation in K562/vector cells, respectively. In contrast, PBTD-1 and -3-induced caspase-3 activation and apoptosis were inhibited in K562/Bcl-2. Furthermore, Bcl-2 overexpressing cells exhibited less cytocrome c release during PBTDs-induced apoptosis.

CONCLUSION

These results indicate that PBTDs effectively induce apoptosis of K562 leukemia cells through the activation of caspase cascades. In addition, these findings indicate that Bcl-2 inhibits PBTD-1 and -3 induced-apoptosis via a mechanism that interferes with cytocrome c release, and the activity of caspase-3, which is involved in the execution of apoptosis.

Authors+Show Affiliations

Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy. gmarfe1@virgilio.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17996085

Citation

Marfe, Gabriella, et al. "PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) Induce Apoptosis in K562 Cells." BMC Cancer, vol. 7, 2007, p. 207.
Marfe G, Di Stefano C, Silvestri R, et al. PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) induce apoptosis in K562 cells. BMC Cancer. 2007;7:207.
Marfe, G., Di Stefano, C., Silvestri, R., Abruzzese, E., Catalano, G., Di Renzo, L., Filomeni, G., Giorda, E., La Regina, G., Morgante, E., Ciriolo, M. R., Russo, M. A., Amadori, S., & Sinibaldi-Salimei, P. (2007). PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) induce apoptosis in K562 cells. BMC Cancer, 7, 207.
Marfe G, et al. PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) Induce Apoptosis in K562 Cells. BMC Cancer. 2007 Nov 9;7:207. PubMed PMID: 17996085.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) induce apoptosis in K562 cells. AU - Marfe,Gabriella, AU - Di Stefano,Carla, AU - Silvestri,Romano, AU - Abruzzese,Elisabetta, AU - Catalano,Gianfranco, AU - Di Renzo,Livia, AU - Filomeni,Giuseppe, AU - Giorda,Ezio, AU - La Regina,Giuseppe, AU - Morgante,Emanuela, AU - Ciriolo,Maria Rosa, AU - Russo,Matteo Antonio, AU - Amadori,Sergio, AU - Sinibaldi-Salimei,Paola, Y1 - 2007/11/09/ PY - 2007/07/06/received PY - 2007/11/09/accepted PY - 2007/11/13/pubmed PY - 2008/3/25/medline PY - 2007/11/13/entrez SP - 207 EP - 207 JF - BMC cancer JO - BMC Cancer VL - 7 N2 - BACKGROUND: The objective of this study was to gain insight into the molecular mechanism of induced cell death (apoptosis) by PYRROLO [1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) series compounds, using human (K562) cells as a model. METHODS: We focused our attention on some members of the PBTDs family to test their potential apoptotic activity in K562 cells. Important apoptotic activity was demonstrated, as evidenced by the concentration and percentage of cell death quantified by measuring PI-uptake by flow cytometry, and DNA fragmentation analyzed by agarose gel electrophoresis, generating a characteristic ladder pattern of discontinuous DNA fragments. The expression of Bcl-2 family was tested using western blotting and transfection method. RESULTS: PBTDs-mediated suppression of K562 cell proliferation was induced by apoptosis characterized by the appearance of DNA fragmentation and was associated with the poly(ADP-ribose)polymerase (PARP) cleavage. PBTD-1 and -3 treatment resulted in caspase-3 activation through down-regulation of Bcl-2 and up-regulation of Bax. Furthermore, we used K562/vector and K562/bcl-2 cells, which were generated by transfection of the cDNA of the Bcl-2 gene. As compared with K562/vector, K562/Bcl-2 cells exhibited a 4-fold greater expression of Bcl-2. Treatment with 10 muM PBTD-1 and -3 for 24 h produced morphological features of apoptosis and DNA fragmentation in K562/vector cells, respectively. In contrast, PBTD-1 and -3-induced caspase-3 activation and apoptosis were inhibited in K562/Bcl-2. Furthermore, Bcl-2 overexpressing cells exhibited less cytocrome c release during PBTDs-induced apoptosis. CONCLUSION: These results indicate that PBTDs effectively induce apoptosis of K562 leukemia cells through the activation of caspase cascades. In addition, these findings indicate that Bcl-2 inhibits PBTD-1 and -3 induced-apoptosis via a mechanism that interferes with cytocrome c release, and the activity of caspase-3, which is involved in the execution of apoptosis. SN - 1471-2407 UR - https://www.unboundmedicine.com/medline/citation/17996085/PYRROLO[12_b][125]BENZOTHIADIAZEPINES__PBTDs__induce_apoptosis_in_K562_cells_ L2 - https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-7-207 DB - PRIME DP - Unbound Medicine ER -