Gallium maltolate and cisplatin co-treatment effectively targets triple-negative breast cancer in spheroid and mouse models

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks targeted therapies and is characterized by high invasiveness and metastatic potential. Our previous work demonstrated that GaM (gallium maltolate) blocks cell cycle progression and impairs ribosomal synthesis in TNBC cells. Moreover, GaM treatment promotes ferroptosis activation, and its combination with cisplatin exhibits synergistic effects. To further evaluate the efficacy of these treatments, we applied them to three-dimensional spheroid and mouse models. Two types of spheroids were generated: one composed solely of TNBC cells (MDA-MB-231) and the other a co-culture with normal breast cells (MCF10A). In both MDA/MCF10A and MDA-MB-231 spheroids, we observed enhanced p53 activation and increased p21 expression, with the effects being more pronounced in the MDA-MB-231 spheroids. These effects were stronger with the combination treatment than with either treatment alone. Similar results were observed in a xenograft model, where tumors formed from MDA-MB-231 cells in nude mice. The combination therapy reduced tumor size to a similar extent as cisplatin alone and did not cause adverse effects in mice. The combination therapy induced apoptosis, nucleolar stress, and ferroptosis. Additionally, the treatment inhibited cell migration and metastasis - by increasing E-cadherin levels and reducing metalloproteases. These findings provide a strong foundation for further mechanistic studies and potential clinical applications.