Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest.
BACKGROUND: Due to the functional defects in apoptosis signaling molecules or deficient activation of apoptosis pathways, leukemia has become an aggressive disease with poor prognosis. Although the majority of leukemia patients initially respond to chemotherapy, relapse is still the leading cause of...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3724874?pdf=render |
| _version_ | 1819237800166293504 |
|---|---|
| author | Chandagirikoppal V Kavitha Mridula Nambiar Pavan B Narayanaswamy Elizabeth Thomas Ujjwal Rathore Channapillekoppalu S Ananda Kumar Bibha Choudhary Kanchugarakoppal S Rangappa Sathees C Raghavan |
| author_facet | Chandagirikoppal V Kavitha Mridula Nambiar Pavan B Narayanaswamy Elizabeth Thomas Ujjwal Rathore Channapillekoppalu S Ananda Kumar Bibha Choudhary Kanchugarakoppal S Rangappa Sathees C Raghavan |
| author_sort | Chandagirikoppal V Kavitha |
| collection | DOAJ |
| description | BACKGROUND: Due to the functional defects in apoptosis signaling molecules or deficient activation of apoptosis pathways, leukemia has become an aggressive disease with poor prognosis. Although the majority of leukemia patients initially respond to chemotherapy, relapse is still the leading cause of death. Hence targeting apoptosis pathway would be a promising strategy for the improved treatment of leukemia. Hydantoin derivatives possess a wide range of important biological and pharmacological properties including anticancer properties. Here we investigated the antileukemic activity and mechanism of action of one of the potent azaspiro hydantoin derivative, (ASHD). MATERIALS AND METHODS: To investigate the antileukemic efficacy of ASHD, we have used MTT assay, cell cycle analysis by FACS, tritiated thymidine incorporation assay, Annexin V staining, JC1 staining and western blot analysis. RESULTS: Results showed that ASHD was approximately 3-fold more potent than the parent compounds in inducing cytotoxicity. Tritiated thymidine assay in conjunction with cell cycle analysis suggests that ASHD inhibited the growth of leukemic cells. The limited effect of ASHD on cell viability of normal cells indicated that it may be specifically directed to cancer cells. Translocation of phosphatidyl serine, activation of caspase 3, caspase 9, PARP, alteration in the ratio of BCL2/BAD protein expression as well as the loss of mitochondrial membrane potential suggests activation of the intrinsic pathway of apoptosis. CONCLUSION: These results could facilitate the future development of novel hydantoin derivatives as chemotherapeutic agents for leukemia. |
| first_indexed | 2024-12-23T13:26:05Z |
| format | Article |
| id | doaj.art-88a470dfdf3f4388bd6cb45ad3301d82 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T13:26:05Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-88a470dfdf3f4388bd6cb45ad3301d822022-12-21T17:45:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e6910310.1371/journal.pone.0069103Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest.Chandagirikoppal V KavithaMridula NambiarPavan B NarayanaswamyElizabeth ThomasUjjwal RathoreChannapillekoppalu S Ananda KumarBibha ChoudharyKanchugarakoppal S RangappaSathees C RaghavanBACKGROUND: Due to the functional defects in apoptosis signaling molecules or deficient activation of apoptosis pathways, leukemia has become an aggressive disease with poor prognosis. Although the majority of leukemia patients initially respond to chemotherapy, relapse is still the leading cause of death. Hence targeting apoptosis pathway would be a promising strategy for the improved treatment of leukemia. Hydantoin derivatives possess a wide range of important biological and pharmacological properties including anticancer properties. Here we investigated the antileukemic activity and mechanism of action of one of the potent azaspiro hydantoin derivative, (ASHD). MATERIALS AND METHODS: To investigate the antileukemic efficacy of ASHD, we have used MTT assay, cell cycle analysis by FACS, tritiated thymidine incorporation assay, Annexin V staining, JC1 staining and western blot analysis. RESULTS: Results showed that ASHD was approximately 3-fold more potent than the parent compounds in inducing cytotoxicity. Tritiated thymidine assay in conjunction with cell cycle analysis suggests that ASHD inhibited the growth of leukemic cells. The limited effect of ASHD on cell viability of normal cells indicated that it may be specifically directed to cancer cells. Translocation of phosphatidyl serine, activation of caspase 3, caspase 9, PARP, alteration in the ratio of BCL2/BAD protein expression as well as the loss of mitochondrial membrane potential suggests activation of the intrinsic pathway of apoptosis. CONCLUSION: These results could facilitate the future development of novel hydantoin derivatives as chemotherapeutic agents for leukemia.http://europepmc.org/articles/PMC3724874?pdf=render |
| spellingShingle | Chandagirikoppal V Kavitha Mridula Nambiar Pavan B Narayanaswamy Elizabeth Thomas Ujjwal Rathore Channapillekoppalu S Ananda Kumar Bibha Choudhary Kanchugarakoppal S Rangappa Sathees C Raghavan Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. PLoS ONE |
| title | Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. |
| title_full | Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. |
| title_fullStr | Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. |
| title_full_unstemmed | Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. |
| title_short | Propyl-2-(8-(3,4-difluorobenzyl)-2',5'-dioxo-8-azaspiro[bicyclo[3.2.1] octane-3,4'-imidazolidine]-1'-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. |
| title_sort | propyl 2 8 3 4 difluorobenzyl 2 5 dioxo 8 azaspiro bicyclo 3 2 1 octane 3 4 imidazolidine 1 yl acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest |
| url | http://europepmc.org/articles/PMC3724874?pdf=render |
| work_keys_str_mv | AT chandagirikoppalvkavitha propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT mridulanambiar propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT pavanbnarayanaswamy propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT elizabeththomas propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT ujjwalrathore propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT channapillekoppalusanandakumar propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT bibhachoudhary propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT kanchugarakoppalsrangappa propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest AT satheescraghavan propyl2834difluorobenzyl25dioxo8azaspirobicyclo321octane34imidazolidine1ylacetateinducesapoptosisinhumanleukemiacellsthroughmitochondrialpathwayfollowingcellcyclearrest |