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Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116.

ABSTRACT: Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(iv) conjugates derived from Pt(ii) drug (cisplatin or oxaliplatin) and niflumic acid, complexes 1 and 2, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex 2 afforded higher cytotoxicity than 1 and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, 2 was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of 2 is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that 2 inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.

SUBMITTER: Ma ZY

PROVIDER: S-EPMC11342162 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116.

Ma Zhong-Ying ZY Ding Xiao-Jing XJ Zhu Zhen-Zhen ZZ Chen Qian Q Wang Dong-Bo DB Qiao Xin X Xu Jing-Yuan JY

RSC medicinal chemistry 20240801

Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(iv) conjugates derived from Pt(ii) drug (cisplatin or oxaliplatin) and niflumic acid, complexes 1 and 2, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex 2 afforded higher cytotoxicity than 1 and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A ...[more]

PMID: 39185449

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Project description:Pt(ii) chemotherapeutic complexes have been used as predominant anticancer drugs for nearly fifty years. Currently there are three FDA-approved chemotherapeutic Pt(ii) complexes: cisplatin, carboplatin, and oxaliplatin. Until recently, it was believed that all three complexes induced cellular apoptosis through the DNA damage response pathway. Studies within the last decade, however, suggest that oxaliplatin may instead induce cell death through a unique nucleolar stress pathway. Pt(ii)-induced nucleolar stress is not well understood and further investigation of this pathway may provide both basic knowledge about nucleolar stress as well as insight for more tunable Pt(ii) chemotherapeutics. Through a previous structure-function analysis, it was determined that nucleolar stress induction is highly sensitive to modifications at the 4-position of the 1,2-diaminocyclohexane (DACH) ring of oxaliplatin. Specifically, more flexible and less rigid substituents (methyl, ethyl, propyl) induce nucleolar stress, while more rigid and bulkier substituents (isopropyl, acetamide) do not. These findings suggest that a click-capable functional group can be installed at the 4-position of the DACH ring while still inducing nucleolar stress. Herein, we report novel click-capable azide-modified oxaliplatin mimics that cause nucleolar stress. Through NPM1 relocalization, fibrillarin redistribution, and γH2AX studies, key differences have been identified between previously studied click-capable cisplatin mimics and these novel click-capable oxaliplatin mimics. These complexes provide new tools to identify cellular targets and localization through post-treatment Cu-catalyzed azide-alkyne cycloaddition and may help to better understand Pt(ii)-induced nucleolar stress. To our knowledge, these are the first reported oxaliplatin mimics to include an azide handle, and cis-[(1R,2R,4S) 4-methylazido-1,2-cyclohexanediamine]dichlorido platinum(ii) is the first azide-functionalized oxaliplatin derivative to induce nucleolar stress.

Dataset Information

Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116.

Publications

Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116.

Similar Datasets

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