Cytostatic Activity of a Novel Synthetic Curcumoberberine Conjugate and its Pharmacological Interaction with Doxorubicin in Breast Cancer Cell Cultures

Abstract

Introduction. The persistent challenge of treating breast cancer (BC) drives the search for novel antitumor agents. Plant secondary metabolites offer significant therapeutic potential, but their clinical application is often hindered by low bioavailability, creating a need for the rational design of new, water-soluble molecules.

Aim. To evaluate the in vitro cytotoxic activity of a novel, synthetic, water-soluble compound named curcumoberberine against established breast cancer cell lines, both as a monotherapy and in combination with doxorubicin.

Materials and Methods. The antiproliferative effects of the synthesized conjugate were assessed on the following BC cell lines: MDA-MB-453 (HER2+), BT-474 (luminal, HER2-expressing), and BT-20 (triple-negative), as well as on normal skin fibroblasts. Cells were incubated for 48 hours with curcumoberberine (0.195 to 50 μM), doxorubicin, or their combinations. Viability was measured using a colorimetric MTT assay, and half-maximal inhibitory concentration (IC₅₀) values were calculated. The nature of the drug interaction (synergy, additivity, or antagonism) was analyzed using the Zero Interaction Potency (ZIP) model in the SynergyFinderPlus software.

Results. As a monotherapy, curcumoberberine demonstrated moderate dose-dependent cytostatic activity. The IC₅₀ values were 54.2 ± 13.3 μM for the MDA-MB-453 line, 68.0 ± 5.7 μM for BT-20, and 70.5 ± 10.4 μM for BT-474. A statistically significant decrease in tumor cell viability compared to non-tumor fibroblasts was recorded predominantly at concentrations of 25–50 μM. The combined application of curcumoberberine and doxorubicin did not exhibit synergy in any tested cell line. The most pronounced pharmacological antagonism was observed in BT-474 cells (integral synergy score: –19.0), where the drug combination induced a hormetic effect (hormesis). Interactions characterized by mild antagonism (scores between –8 and –10) were registered in BT-20 and MDA-MB-453 cultures.

Conclusion. The novel water-soluble conjugate, curcumoberberine, exhibits dose-dependent cytostatic activity against BC cell cultures at concentrations of 25–50 μM. Its combined use with doxorubicin is not recommended due to the development of pronounced pharmacological antagonism. Further investigation into the intracellular metabolism of this agent and its testing in combination with drugs from other pharmacological classes is warranted.