Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro
Topotecan, a topoisomerase I inhibitor, is an anticancer drug widely used in the therapy of lung, ovarian, colorectal, and breast adenocarcinoma. Due to the primary dose-limiting toxicity of topotecan, which is myelosuppressive, it is necessary to identify other chemotherapeutic agents that can work...
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2016
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| Online Access: | http://hdl.handle.net/10725/8069 http://dx.doi.org/10.1055/s-0035-1558289 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1558289 |
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| _version_ | 1864513483831246848 |
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| author | Khalife, Rana |
| author2 | Hodroj, Mohammad Hassan Fakhoury, Rajaa Rizk, Sandra |
| author2_role | author author author |
| author_facet | Khalife, Rana Hodroj, Mohammad Hassan Fakhoury, Rajaa Rizk, Sandra |
| author_role | author |
| dc.creator.none.fl_str_mv | Khalife, Rana Hodroj, Mohammad Hassan Fakhoury, Rajaa Rizk, Sandra |
| dc.date.none.fl_str_mv | 2016 2018-06-21T06:47:29Z 2018-06-21T06:47:29Z 2018-06-21 |
| dc.identifier.none.fl_str_mv | 1439-0221 http://hdl.handle.net/10725/8069 http://dx.doi.org/10.1055/s-0035-1558289 Khalife, R., Hodroj, M. H., Fakhoury, R., & Rizk, S. (2016). Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro. Planta medica, 82(04), 312-321. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1558289 |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Planta Medica |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | Topotecan, a topoisomerase I inhibitor, is an anticancer drug widely used in the therapy of lung, ovarian, colorectal, and breast adenocarcinoma. Due to the primary dose-limiting toxicity of topotecan, which is myelosuppressive, it is necessary to identify other chemotherapeutic agents that can work synergistically with topotecan to increase its efficacy and limit its toxicity. Many studies have shown synergism upon the combination of topotecan with other chemotherapeutic agents such as gemcitabine. Other studies have demonstrated that pre-exposing cells to naturally occurring compounds such as thymoquinone, followed by gemcitabine or oxaliplatin, resulted in higher growth inhibition compared to treatment with gemcitabine or oxaliplatin alone. Our aim was to elucidate the underlying mechanism of action of topotecan in the survival and apoptotic pathways in human colon cancer cell lines in comparison to thymoquinone, to study the proapoptotic and antiproliferative effects of thymoquinone on the effectiveness of the chemotherapeutic agent topotecan, and to investigate the potential synergistic effect of thymoquinone with topotecan. Cells were incubated with different topotecan and thymoquinone concentrations for 24 and 48 hours in order to determine the IC50 for each drug. Combined therapy was then tested with ± 2 values for the IC50 of each drug. The reduction in proliferation was significantly dose- and time-dependent. After determining the best combination (40 µM thymoquinone and 0.6 µM topotecan), cell proteins were extracted after treatment, and the expression levels of B-cell lymphoma 2 and of its associated X protein, proteins p53 and p21, and caspase-9, caspase-3, and caspase-8 were studied by Western blot. In addition, cell cycle analysis and annexin/propidium iodide staining were performed. Both drugs induced apoptosis through a p53-independent mechanism, whereas the expression of p21 was only seen in thymoquinone treatment. Cell cycle arrest in the S phase was detected with each compound separately, while combined treatment only increased the production of fragmented DNA. Both compounds induced apoptosis through the extrinsic pathway after 24 hours; however, after 48 hours, the intrinsic pathway was activated by topotecan treatment only. In conclusion, thymoquinone increased the effectiveness of the chemotherapeutic reagent topotecan by inhibiting proliferation and lowering toxicity through p53- and Bax/Bcl2-independent mechanisms. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_9ca4c8d14b99271abd9f986e61cc7432 |
| identifier_str_mv | 1439-0221 Khalife, R., Hodroj, M. H., Fakhoury, R., & Rizk, S. (2016). Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro. Planta medica, 82(04), 312-321. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/8069 |
| publishDate | 2016 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitroKhalife, RanaHodroj, Mohammad HassanFakhoury, RajaaRizk, SandraTopotecan, a topoisomerase I inhibitor, is an anticancer drug widely used in the therapy of lung, ovarian, colorectal, and breast adenocarcinoma. Due to the primary dose-limiting toxicity of topotecan, which is myelosuppressive, it is necessary to identify other chemotherapeutic agents that can work synergistically with topotecan to increase its efficacy and limit its toxicity. Many studies have shown synergism upon the combination of topotecan with other chemotherapeutic agents such as gemcitabine. Other studies have demonstrated that pre-exposing cells to naturally occurring compounds such as thymoquinone, followed by gemcitabine or oxaliplatin, resulted in higher growth inhibition compared to treatment with gemcitabine or oxaliplatin alone. Our aim was to elucidate the underlying mechanism of action of topotecan in the survival and apoptotic pathways in human colon cancer cell lines in comparison to thymoquinone, to study the proapoptotic and antiproliferative effects of thymoquinone on the effectiveness of the chemotherapeutic agent topotecan, and to investigate the potential synergistic effect of thymoquinone with topotecan. Cells were incubated with different topotecan and thymoquinone concentrations for 24 and 48 hours in order to determine the IC50 for each drug. Combined therapy was then tested with ± 2 values for the IC50 of each drug. The reduction in proliferation was significantly dose- and time-dependent. After determining the best combination (40 µM thymoquinone and 0.6 µM topotecan), cell proteins were extracted after treatment, and the expression levels of B-cell lymphoma 2 and of its associated X protein, proteins p53 and p21, and caspase-9, caspase-3, and caspase-8 were studied by Western blot. In addition, cell cycle analysis and annexin/propidium iodide staining were performed. Both drugs induced apoptosis through a p53-independent mechanism, whereas the expression of p21 was only seen in thymoquinone treatment. Cell cycle arrest in the S phase was detected with each compound separately, while combined treatment only increased the production of fragmented DNA. Both compounds induced apoptosis through the extrinsic pathway after 24 hours; however, after 48 hours, the intrinsic pathway was activated by topotecan treatment only. In conclusion, thymoquinone increased the effectiveness of the chemotherapeutic reagent topotecan by inhibiting proliferation and lowering toxicity through p53- and Bax/Bcl2-independent mechanisms.PublishedN/A2018-06-21T06:47:29Z2018-06-21T06:47:29Z20162018-06-21Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1439-0221http://hdl.handle.net/10725/8069http://dx.doi.org/10.1055/s-0035-1558289Khalife, R., Hodroj, M. H., Fakhoury, R., & Rizk, S. (2016). Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro. Planta medica, 82(04), 312-321.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttps://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1558289enPlanta Medicainfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/80692021-03-19T10:43:08Z |
| spellingShingle | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro Khalife, Rana |
| status_str | publishedVersion |
| title | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro |
| title_full | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro |
| title_fullStr | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro |
| title_full_unstemmed | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro |
| title_short | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro |
| title_sort | Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro |
| url | http://hdl.handle.net/10725/8069 http://dx.doi.org/10.1055/s-0035-1558289 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1558289 |