Flavonoid Monomers as Potent, Nontoxic, and Selective Modulators of the Breast Cancer Resistance Protein (ABCG2).

We synthesize various substituted triazole-containing flavonoids and identify potent, nontoxic, and highly selective BCRP inhibitors. Ac18Az8, Ac32Az19, and Ac36Az9 possess m-methoxycarbonylbenzyloxy substitution at C-3 of the flavone moiety and substituted triazole at C-4' of the B-ring. They show low toxicity (IC50 toward L929 > 100 µM), potent BCRP-inhibitory activity (EC50 = 1-15 nM), and high BCRP selectivity (BCRP selectivity over MRP1 and P-gp > 67-714). They inhibit the efflux activity of BCRP, elevate the intracellular drug accumulation, and restore the drug sensitivity of BCRP-overexpressing cells. Like Ko143, Ac32Az19 remarkably exhibits a 100% 5D3 shift, indicating that it can bind and cause a conformational change of BCRP. Moreover, it significantly reduces the abundance of functional BCRP dimers/oligomers by half to retain more mitoxantrone in the BCRP-overexpressing cell line and that may account for its inhibitory activity. They are promising candidates to be developed into combination therapy to overcome MDR cancers with BCRP overexpression.

Disruption of SND1-MTDH Interaction by a High Affinity Peptide Results in SND1 Degradation and Cytotoxicity to Breast Cancer Cells In Vitro and In Vivo.

Staphylococcal nuclease domain-containing protein 1 (SND1) is a multifunctional oncoprotein overexpressed in breast cancer. Binding of metadherin (MTDH) to SND1 results in the stabilization of SND1 and is important in the initiation and progression of breast cancer. Disruption of such interaction is a potential therapeutic for breast cancer. SN1/2 domain of SND1 was used as bait in a phage display screening to identify a 12-amino acid peptide 4-2. The activity of peptide 4-2 was evaluated by ELISA, coimmunoprecipitation, MTS, Western blot analysis, and xenograft mouse model. Peptide 4-2 could disrupt SND1-MTDH interaction. Cell penetrating derivative of peptide 4-2 (CPP-4-2) could penetrate and kill breast cancer cells by disrupting SND1-MTDH interaction and degrading SND1. Tryptophan 10 (W10) of peptide 4-2 was essential in mediating cytotoxicity, SND1 interaction, SND1-MTDH disruption, and SND1 degradation. CPP-4-2 could inhibit the growth of breast cancer in a xenograft mouse model. The SND1-interacting peptide 4-2 could kill breast cancer cells both in vitro and in vivo by interacting with SND1, disrupting SND1-MTDH interaction, and inducing SND1 degradation. W10 was an essential amino acid in the activity of peptide 4-2.