Staff View: New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family

New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family

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 signa...

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Main Authors:	Simon, Samson Eugin, Usman, Ahmed , Saad, Syed Muhammad, Ayaz, Anwar , Khan, Khalid Mohammed, Tan, Ee Wern , Tan, Kuan Onn
Format:	Article
Published:	Elsevier 2022
Subjects:	QH Natural history RC Internal medicine RM Therapeutics. Pharmacology
Online Access:	http://eprints.sunway.edu.my/3113/ https://doi.org/10.1016/j.bmcl.2022.128731
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spelling	my.sunway.eprints.31132024-08-13T05:54:29Z http://eprints.sunway.edu.my/3113/ New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family Simon, Samson Eugin Usman, Ahmed * Saad, Syed Muhammad Ayaz, Anwar * Khan, Khalid Mohammed Tan, Ee Wern * Tan, Kuan Onn * QH Natural history RC Internal medicine RM Therapeutics. Pharmacology 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. Elsevier 2022 Article PeerReviewed 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 https://doi.org/10.1016/j.bmcl.2022.128731 10.1016/j.bmcl.2022.128731
institution	Sunway University
building	Sunway Campus Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Sunway University
content_source	Sunway Institutional Repository
url_provider	http://eprints.sunway.edu.my/
topic	QH Natural history RC Internal medicine RM Therapeutics. Pharmacology
spellingShingle	QH Natural history RC Internal medicine RM Therapeutics. Pharmacology Simon, Samson Eugin Usman, Ahmed * Saad, Syed Muhammad Ayaz, Anwar * Khan, Khalid Mohammed Tan, Ee Wern * Tan, Kuan Onn * New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family
description	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.
format	Article
author	Simon, Samson Eugin Usman, Ahmed * Saad, Syed Muhammad Ayaz, Anwar * Khan, Khalid Mohammed Tan, Ee Wern * Tan, Kuan Onn *
author_facet	Simon, Samson Eugin Usman, Ahmed * Saad, Syed Muhammad Ayaz, Anwar * Khan, Khalid Mohammed Tan, Ee Wern * Tan, Kuan Onn *
author_sort	Simon, Samson Eugin
title	New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family
title_short	New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family
title_full	New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family
title_fullStr	New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family
title_full_unstemmed	New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family
title_sort	new synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the bcl-2 family
publisher	Elsevier
publishDate	2022
url	http://eprints.sunway.edu.my/3113/ https://doi.org/10.1016/j.bmcl.2022.128731
_version_	1808975643696693248
score	13.222552

New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family

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