Abstract 4905: Anticancer activity and paraptosis induction of novel bipyridine-silver(I) compounds against resistant colorectal and ovarian cancer cell lines
Authors: Stefanelli Alessia , Teixeira Ricardo G. , Pilon Adhan , Warmers Rebecca , Ott Ingo , Kowol Christian R. , Brozovic Anamaria , Tomaz Ana Isabel , Valente Andreia , Heffeter Petra 
Published: April 2023

Background: Platinum-based anticancer drugs (e.g. Carboplatin and Oxaliplatin) are frequently applied in chemotherapy regimens against several types of cancer including ovarian carcinoma (OC) and colorectal carcinoma (CRC). However, intrinsic or acquired tumor resistance severely limit their clinical application. Here, we investigated the anticancer activity of several novel silver(I) 2,2’-bipyridine derivatives, containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands and tested their potential to overcome platinum resistance.

Methods: Cytotoxicity and cross resistance profiles of the newly synthesized compounds were tested against two OC models (SKOV-3 and MES-OV), a CRC model (HCT-116) and their corresponding sublines resistant to carboplatin or oxaliplatin, as well as non-malignant fibroblasts (F331) via an MTT-based cell viability assay after 72 h continuous drug exposure. Moreover, the intracellular levels of silver were measured via ICP-MS. In addition, thioredoxin reductase (TrxR) inhibition properties, impact on cell cycle distribution and apoptosis induction potential were investigated via multiple molecular biological methods. Morphological changes induced by the silver compounds were characterized via spinning disk confocal microscopy.

Results: All tested compounds displayed pronounced anticancer activity and cancer cell selectivity. Moreover, cell intrinsic resistance to carboplatin or oxaliplatin was not impacting on the cytotoxic activity of the compounds. Noteworthy, MES-OV and HCT-116 cells showed exceptional sensitivity to several silver(I) 2,2’-bipyridine derivatives with a 1,2-bis(diphenylphosphino)ethane (dppe) (AP-compounds). This sensitivity was not based on enhanced drug uptake, pronounced TrxR inhibition nor apoptosis induction or cell cycle arrest. In contrast, hypersensitive cells displayed pronounced endoplasmic reticulum (ER)-derived vesicles together with multiple others hallmarks of paraptotic cell death.

Conclusion: Our findings did not only demonstrate that the new silver compounds were unaffected by cancer cell intrinsic resistance mechanisms to platinum-based chemotherapy, but also indicated a high vulnerability of tumor (sub)types towards these bipyridine silver complexes. This hypersensitivity is based on the induction of paraptosis, a novel form of programmed cell death. To summarize, these silver compounds represent a new class of promising anticancer drugs, which demand further preclinical development.

Citation Format: Alessia Stefanelli, Ricardo G. Teixeira, Adhan Pilon, Rebecca Warmers, Ingo Ott, Christian R. Kowol, Anamaria Brozovic, Ana Isabel Tomaz, Andreia Valente, Petra Heffeter. Anticancer activity and paraptosis induction of novel bipyridine-silver(I) compounds against resistant colorectal and ovarian cancer cell lines. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4905.