Simon, Samson Eugin and Usman, Ahmed * and Saad, Syed Muhammad and Ayaz, Anwar * and Khan, Khalid Mohammed and Tan, Ee Wern * and Tan, Kuan Onn * (2022) New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family. Bioorganic and Medicinal Chemistry, 67. ISSN 0968-0896
Full text not available from this repository. (Request a copy)Abstract
Chemo-resistant cancer cells acquire robust growth potential through cell signaling mechanisms such as the down-regulation of tumor suppressors and the up-regulation of pro-survival proteins, respectively. To overcome chemo-resistance of cancer, small molecule drugs that interact with the cell signaling proteins to enhance sensitization of cancer cells toward cancer therapies are likely to be effective for the treatment of chemo-drug resistant cancer. To identify high potency small molecules, a series of ten novel phenylquinazoline derivatives were synthesized to determine their cellular effects in MCF-7 and MCF-7- cisplatin-resistant (CR) human breast cancer cells which led to the identification of two bioactive compounds, SMS-IV-20 and SMS-IV-40, that exhibited an elevated level of cytotoxicity against the human breast cancer cells and spheroid cells. In addition, both compounds enhanced chemo-sensitization of the human breast cancer cells that were genetically engineered to express the tumor suppressor and pro-apoptotic proteins, MOAP-1, Bax, and RASSF1a (MBR), suggesting that the compounds interact with the MBR signaling pathway. Furthermore, when MCF-7-CR cells were treated with SMS-IV-20 and SMS-IV-40 in the presence of ABT-737, a BCL-XL and BCL-2 inhibitor, enhanced chemo-sensitization was observed, suggesting SMS-IV-20 and SMS-IV-40 exert antagonistic activity to regulate the functional activity of BCL-2 and BCL-XL. Western blot analysis showed that both SMS-IV-20 and SMS-IV-40 induced down-regulation of BCL-2 or both BCl-2 and BCL-XL expression, respectively while promoting the release of mitochondrial Cytochrome C. Taken together, the data showed that SMS-IV-20 and SMS-IV-40 are potent activators of apoptosis that enhance chemo-sensitization through their antagonistic actions on the pro-survival activity of the BCl-2 family in human cancer cells.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | apoptosis; BCL-2; BCL-XL; mitochondria; synthesis of phenylquinazoline derivatives. |
| Subjects: | Q Science > QH Natural history R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Others > Non Sunway Academics Sunway University > School of Medical and Life Sciences [formerly School of Healthcare and Medical Sciences until 2020] > Dept. Biological Sciences |
| Depositing User: | Ms Yong Yee Chan |
| Related URLs: | |
| Date Deposited: | 13 Aug 2024 05:54 |
| Last Modified: | 13 Aug 2024 05:54 |
| URI: | http://eprints.sunway.edu.my/id/eprint/3113 |
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