Pt(iv) derivatives of cisplatin and oxaliplatin bearing an EMT-related TMEM16A/COX-2-selective dual inhibitor against colorectal cancer cells HCT116.
Zhong-Ying MaXiao-Jing DingZhen-Zhen ZhuQian ChenDong-Bo WangXin QiaoJing-Yuan XuPublished in: RSC medicinal chemistry (2024)
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.
Keyphrases
- cell cycle arrest
- pi k akt
- cell death
- signaling pathway
- dna damage
- cell proliferation
- small cell lung cancer
- epithelial mesenchymal transition
- oxidative stress
- poor prognosis
- induced apoptosis
- epidermal growth factor receptor
- cell free
- cancer therapy
- emergency department
- stem cells
- binding protein
- breast cancer cells
- endoplasmic reticulum stress