Enhancing Chemotherapy in Ovarian Cancer with Supramolecular Self-Associating Amphiphiles

Ovarian cancer is a leading cause of gynaecological cancer mortality, due to a late-stage diagnosis and the emergence of resistance to platinum-based therapies. These challenges highlight the need for novel strategies that can enhance the efficacy of existing treatments. Supramolecular self- associating amphiphiles (SSAs) are novel compounds hypothesised to selectively interact with cancer cell membranes. This study aimed to investigate the effects of SSA compound 48 in combination with cisplatin, olaparib and paclitaxel in the cisplatin sensitive A2780, and PEO1 human ovarian cancer cell lines, along with the cisplatin resistant A2780 cisR subline. Cell viability assays indicated that compound 48 exhibited limited activity as a single agent. However, combination studies demonstrated enhanced cytotoxic effects when 48 was used alongside selected chemotherapeutics, with outcomes dependent on treatment strategy. Sequential exposure appeared more effective than co-formulation, suggesting treatment scheduling may play a key role in optimising responses. Mechanistic investigations indicated that 48 can induce cellular stress responses associated with DNA damage and apoptosis, although combination treatments did not consistently intensify these effects, implying that additional mechanisms may contribute to the observed interactions. Overall, while 48 exhibits limited anticancer activity alone, it has the potential to enhance the cytotoxicity of selected chemotherapies. Further mechanistic studies are required to clarify its mode of actions and

evaluate its potential as an adjuvant in ovarian cancer therapy.