Enhanced potency of a chloro-substituted polyaromatic platinum(II) complex and its platinum(IV) prodrug against lung cancer

Joy Baz; Aleen Khoury; Maria George Elias; Najwa Mansour; Stephanie Mehanna; Omar Hammoud; Christopher P Gordon; Robin I Taleb; Janice R Aldrich-Wright; Costantine F Daher

doi:10.1016/j.cbi.2023.110834

Enhanced potency of a chloro-substituted polyaromatic platinum(II) complex and its platinum(IV) prodrug against lung cancer

Chem Biol Interact. 2024 Jan 25:388:110834. doi: 10.1016/j.cbi.2023.110834. Epub 2023 Dec 14.

Affiliations

¹ School of Arts and Sciences, Natural Sciences Department, Lebanese American University, Byblos, Mount Lebanon, Lebanon.
² School of Science, Western Sydney University, Locked Bag 1797, Penrith South, 2751, NSW, Australia.
³ School of Arts and Sciences, Natural Sciences Department, Lebanese American University, Byblos, Mount Lebanon, Lebanon; School of Science, Western Sydney University, Locked Bag 1797, Penrith South, 2751, NSW, Australia.
⁴ School of Science, Western Sydney University, Locked Bag 1797, Penrith South, 2751, NSW, Australia. Electronic address: j.aldrich-wright@westernsydney.edu.au.
⁵ School of Arts and Sciences, Natural Sciences Department, Lebanese American University, Byblos, Mount Lebanon, Lebanon. Electronic address: cdaher@lau.edu.lb.

PMID: 38103879
DOI: 10.1016/j.cbi.2023.110834

Abstract

The present study investigates the anti-neoplastic activity of a platinum (II) complex, Pt(II)5ClSS, and its platinum (IV) di-hydroxido analogue, Pt(IV)5ClSS, against mesenchymal cells (MCs), lung (A549), melanoma (A375) and breast (MDA-MB-231) cancer cells. Both complexes exhibited up to 14-fold improved cytotoxicity compared to cisplatin. NMR was used to determine that ∼25 % of Pt(IV)5ClSS was reduced to Pt(II)5ClSS in the presence of GSH (Glutathione) after 72 h. The complex ¹H NMR spectra acquired for Pt(II)5ClSS with GSH shows evidence of degradation and environmental effects (∼30 %). The prominence of the ¹⁹⁵Pt peak at ∼ -2800 ppm suggests that a significant amount of Pt(II)5ClSS remained in the mixture. Pt(II)5ClSS and Pt(IV)5ClSS have shown exceptional selectivity to cancer cells in comparison to MCs (IC₅₀ > 150 μM). Western blot analysis of Pt(II)5ClSS and Pt(IV)5ClSS on A549 cells revealed significant upregulation of cleaved PARP-1, BAX/Bcl₂ ratio, cleaved caspase 3 and cytochrome thus suggesting apoptosis was induced through the intrinsic pathway. Flow cytometry also revealed significant cell death by apoptosis. Treatment with Pt(II)5ClSS and Pt(IV)5ClSS also showed significant amounts of free radical production while the COMET assay showed that both complexes cause minimal DNA damage. Cellular uptake results via ICP-MS suggest a time-dependent active mode of transport for both complexes with Pt(II)5ClSS being transported at a higher rate compared to Pt(IV)5ClSS. A Dose Escalation Study carried out on BALB/c mice showed that Pt(II)5ClSS and Pt(IV)5ClSS were approximately 8- folds and 12.5-folds, respectively, more tolerated than cisplatin. The present study provides evidence that both complexes may have the characteristics of an efficient and potentially safe anti-tumor drug that could support NSCLC treatment.

Keywords: A549; Cancer therapy; Chemotherapy; Lung cancer; Platinum; Selectivity.

MeSH terms

Animals
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Cisplatin / chemistry
Cisplatin / pharmacology
Lung Neoplasms* / drug therapy
Mice
Platinum / chemistry
Prodrugs* / chemistry

Substances

Cisplatin
Platinum
Prodrugs
Antineoplastic Agents