Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents

Angelico D Aputen; Maria George Elias; Jayne Gilbert; Jennette A Sakoff; Christopher P Gordon; Kieran F Scott; Janice R Aldrich-Wright

doi:10.3390/cancers15092460

Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents

Cancers (Basel). 2023 Apr 26;15(9):2460. doi: 10.3390/cancers15092460.

Authors

Angelico D Aputen¹, Maria George Elias^{1

2}, Jayne Gilbert³, Jennette A Sakoff³, Christopher P Gordon¹, Kieran F Scott^{2

4}, Janice R Aldrich-Wright¹

Affiliations

¹ School of Science, Western Sydney University, Locked Bag 1797, Penrith South, Sydney, NSW 2751, Australia.
² Ingham Institute, Liverpool, Sydney, NSW 2170, Australia.
³ Calvary Mater Newcastle Hospital, Waratah, Newcastle, NSW 2298, Australia.
⁴ School of Medicine, Western Sydney University, Locked Bag 1797, Penrith South, Sydney, NSW 2751, Australia.

Abstract

Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (1-6) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of 1-6. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (5 and 6) were determined to be the most biologically potent, demonstrating GI₅₀ values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI₅₀ value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 1-6 in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy.

Keywords: ROS; acemetacin; chemotherapy; cisplatin; cyclooxygenase-2; cytotoxicity; mitochondria; naproxen; platinum(II); platinum(IV).

Grants and funding

The authors thank Western Sydney University for financial support. Angelico D. Aputen and Maria George Elias were supported through a Western Sydney University Australian Postgraduate Award. The School of Science, Western Sydney University, has supported this work through research funding.