Metal-based drugs have been used in diagnosis and treatment of different types of cancer since the discovery of cisplatin's antineoplastic properties in the 1960’s. Second-generation drugs based on the platinum(II) complex cisplatin, such as carboplatin and oxaliplatin, were developed and used for cancer treatment worldwide. However, platinum(II) drugs typically cause side effects, such as nephrotoxicity, neurotoxicity and myelosuppression, which motivates the search for new drug candidates. Since the platinum(II) and palladium(II) ions have similar characteristics and form analogous compounds, palladium(II) complexes have been also studied as potential anticancer agents. Recently, a new palladium(II) drug named padeliporfin (Tookad®Soluble) has entered the clinic for the treatment of low-risk prostate cancer, which further motivates the investigation of palladium(II) complexes as potential antineoplastic drugs. Adamantanes are a class of organic compounds that consist of a single diamond-like carbon cage. The functionalization of adamantane with an amine group lead to amantadine, which has been used in the clinic as an antiviral and anti-Parkinson drug and has also been evaluated for its anticancer activity.

In this study, we report for the first time the antiproliferative studies of a palladium(II) complex with amantadine (Pd-atd) over squamous cell carcinomas

The Pd-atd complex was prepared following the literature protocol. Briefly, the complex was prepared by the reaction of Li2PdCl4 with amantadine hydrochloride in methanol under stirring and at room temperature. The yellowish solid obtained was collected by filtration, washed with methanol and dried. Yield 72%. The [PdCl2(C10H17N)2] composition was confirmed by chemical and spectroscopic analyses. Squamous cell carcinoma of tongue (SCC-4 and SCC-25) and of hypopharynx (Fadu), and a non-tumoral cell line (HaCat, immortalized keratinocyte) were used in this study. Cells were cultivated following the methodology previously described in the literature. Cell viability was determined by dose-response curves obtained from an MTT assay measuring the absorbance after 48h.

The Pd-atd complex inhibited proliferation of SCC-4 cells with an IC50 of 1.87 µM and it was non-toxic to HaCat cells. Cisplatin, a standard drug, presented an IC50 of 7.02 µM and it was less selective toward HaCat cells in the same experimental conditions.

The promising results of the antiproliferative activities of the Pd-atd complex over SCC-4 cells warrant for additional studies about the potential of application of the complex as an antiproliferative agent for the treatment of squamous cell carcinomas.

This study was supported by grants from the Brazilian Agencies FAPESP (2022/08320-3 and 2021/10265-8 Cancer Theranostics Innovation Center - CEPID), CNPq (309800/2021-8) and Program PPPD at the University of Campinas-UNICAMP (ID number 325141).