Pentagamaboronon-0 increased cytotoxicity of and inhibited metastasis induction by doxorubicin in breast cancer cells

ABSTRACT

Long-term use of doxorubicin (DOX) causes several side effects, especially induction of metastasis, in breast cancercells. Pentagamaboronon-0 (PGB-0) or 2,5-bis(4-boronic acid benzylidene) cyclopentanone is a novel curcumin analogthat exerts cytotoxic effects on Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer cells. Theobjective of this study was to evaluate PGB-0 as a co-chemotherapeutic agent on DOX-induced metastatic breastcancer cells, 4T1. Potential cytotoxic and antimetastatic activities of PGB-0 were screened by molecular docking underPLANTS software, which revealed that the PGB-0 interacted with matrix metalloproteinase-9 (MMP-9) and InhibitorKappa β Kinase (IKKβ). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that PGB-0 andDOX exhibited cytotoxic effects on 4T1 breast cancer cells, with IC50 values of 294 and 2.4 µM, respectively, andsynergistically increased the cytotoxicity of DOX. Results of propidium iodide staining flow cytometry revealed thatthe PGB-0 and its combination with DOX induced cell cycle arrest in the S phase and the G2/M phase, respectively.In addition, PGB-0 and its combination with DOX induced apoptosis. Regarding the antimetastatic activity, a singletreatment with PGB-0 inhibited cell migration, while its combination with DOX inhibited cell migration with morepotency than that with single treatment, as assessed through wound healing assay. Gelatin zymography revealed thatthe PGB-0 and its combination with DOX inhibited MMP-9 activity. Immunoblotting assay showed that the PGB-0and its combination with DOX decreased the expression of Rac1 and p120. In conclusion, PGB-0 increased thecytotoxicity and inhibited the induction of metastasis by DOX in breast cancer cells.