Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancer
Improving the chemotherapy sensitivity of bladder cancer is a current clinical challenge. It is critical to seek out effective combination therapies that include low doses of cisplatin due to its dose-limiting toxicity. This study aims to investigate the cytotoxic effects of the combination therapy...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Saudi Journal of Biological Sciences |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1319562X23000098 |
| _version_ | 1811157874883166208 |
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| author | Hatice Sevim Nalkiran Dilara Akcora Yildiz Faruk Saydam Ali Irfan Guzel Ihsan Nalkiran |
| author_facet | Hatice Sevim Nalkiran Dilara Akcora Yildiz Faruk Saydam Ali Irfan Guzel Ihsan Nalkiran |
| author_sort | Hatice Sevim Nalkiran |
| collection | DOAJ |
| description | Improving the chemotherapy sensitivity of bladder cancer is a current clinical challenge. It is critical to seek out effective combination therapies that include low doses of cisplatin due to its dose-limiting toxicity. This study aims to investigate the cytotoxic effects of the combination therapy including proTAME, a small molecule inhibitor, targeting Cdc-20 and to determine the expression levels of several APC/C pathway-related genes that may play a role in the chemotherapy response of RT-4 (bladder cancer) and ARPE-19 (normal epithelial) cells. The IC20 and IC50 values were determined by MTS assay. The expression levels of apoptosis-associated (Bax and Bcl-2) and APC/C-associated (Cdc-20, Cyclin-B1, Securin, and Cdh-1) genes were assessed by qRT-PCR. Cell colonization ability and apoptosis were examined by clonogenic survival experiment and Annexin V/PI staining, respectively. Low-dose combination therapy showed a superior inhibition effect on RT-4 cells by increasing cell death and inhibiting colony formation. Triple-agent combination therapy further increased the percentage of late apoptotic and necrotic cells compared to the doublet-therapy with gemcitabine and cisplatin. ProTAME-containing combination therapies resulted in an elevation in Bax/Bcl-2 ratio in RT-4 cells, while a significant decrease was observed in proTAME-treated ARPE-19 cells. Cdc-20 expression in proTAME combined treatment groups were found to be decreased compared to their control groups. Low-dose triple-agent combination induced cytotoxicity and apoptosis in RT-4 cells effectively. It is essential to evaluate the role of APC/C pathway-associated potential biomarkers as therapeutic targets and define new combination therapy regimens to achieve improved tolerability in bladder cancer patients in the future. |
| first_indexed | 2024-04-10T05:14:52Z |
| format | Article |
| id | doaj.art-5a9477b28ece4535a6c3b572aa9e92ee |
| institution | Directory Open Access Journal |
| issn | 1319-562X |
| language | English |
| last_indexed | 2024-04-10T05:14:52Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Saudi Journal of Biological Sciences |
| spelling | doaj.art-5a9477b28ece4535a6c3b572aa9e92ee2023-03-09T04:12:47ZengElsevierSaudi Journal of Biological Sciences1319-562X2023-03-01303103564Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancerHatice Sevim Nalkiran0Dilara Akcora Yildiz1Faruk Saydam2Ali Irfan Guzel3Ihsan Nalkiran4Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey; Corresponding author at: Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Islampasa, 53100 Rize, Turkey.Department of Biology, Faculty of Arts and Sciences, Mehmet Akif Ersoy University, Burdur, TurkeyDepartment of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, TurkeyDepartment of Medical Biology, Faculty of Medicine, Bilecik Seyh Edebali University, Bilecik, TurkeyDepartment of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, TurkeyImproving the chemotherapy sensitivity of bladder cancer is a current clinical challenge. It is critical to seek out effective combination therapies that include low doses of cisplatin due to its dose-limiting toxicity. This study aims to investigate the cytotoxic effects of the combination therapy including proTAME, a small molecule inhibitor, targeting Cdc-20 and to determine the expression levels of several APC/C pathway-related genes that may play a role in the chemotherapy response of RT-4 (bladder cancer) and ARPE-19 (normal epithelial) cells. The IC20 and IC50 values were determined by MTS assay. The expression levels of apoptosis-associated (Bax and Bcl-2) and APC/C-associated (Cdc-20, Cyclin-B1, Securin, and Cdh-1) genes were assessed by qRT-PCR. Cell colonization ability and apoptosis were examined by clonogenic survival experiment and Annexin V/PI staining, respectively. Low-dose combination therapy showed a superior inhibition effect on RT-4 cells by increasing cell death and inhibiting colony formation. Triple-agent combination therapy further increased the percentage of late apoptotic and necrotic cells compared to the doublet-therapy with gemcitabine and cisplatin. ProTAME-containing combination therapies resulted in an elevation in Bax/Bcl-2 ratio in RT-4 cells, while a significant decrease was observed in proTAME-treated ARPE-19 cells. Cdc-20 expression in proTAME combined treatment groups were found to be decreased compared to their control groups. Low-dose triple-agent combination induced cytotoxicity and apoptosis in RT-4 cells effectively. It is essential to evaluate the role of APC/C pathway-associated potential biomarkers as therapeutic targets and define new combination therapy regimens to achieve improved tolerability in bladder cancer patients in the future.http://www.sciencedirect.com/science/article/pii/S1319562X23000098Bladder cancerSmall-molecule inhibitorProTAME, CisplatinGemcitabineApoptosis |
| spellingShingle | Hatice Sevim Nalkiran Dilara Akcora Yildiz Faruk Saydam Ali Irfan Guzel Ihsan Nalkiran Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancer Saudi Journal of Biological Sciences Bladder cancer Small-molecule inhibitor ProTAME, Cisplatin Gemcitabine Apoptosis |
| title | Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancer |
| title_full | Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancer |
| title_fullStr | Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancer |
| title_full_unstemmed | Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancer |
| title_short | Targeting the anaphase-promoting complex/cyclosome (APC/C) enhanced antiproliferative and apoptotic response in bladder cancer |
| title_sort | targeting the anaphase promoting complex cyclosome apc c enhanced antiproliferative and apoptotic response in bladder cancer |
| topic | Bladder cancer Small-molecule inhibitor ProTAME, Cisplatin Gemcitabine Apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S1319562X23000098 |
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