Synergistic anticancer and antibacterial effects of novel regimens of phytopolyphenols and repurposing drugs on cultured cells.

Abstract

Background: The increasing incidence of cancers and infectious diseases worldwide presents a significant public health challenge that requires immediate intervention. Our strategy to tackle this issue involves the development of pharmaceutical formulations that combine phytopolyphenols (P), targeted drugs (T), and metal ions (M), collectively referred to as PTM regimens. The diverse pharmacological properties of PTM regimens are hypothesized to effectively reduce the risk factors associated with both cancers and infectious diseases.

Methods: The effects of the pharmaceutical agents on the proliferation of cultured cancer cells and pathogens were assessed after 72 h and 48 h, respectively, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay and optical density at 600 nm (OD600). The synergistic effects of drug combinations were evaluated by combination index (CI), where CI < 1 indicates synergism, CI = 1 indicates addition, and CI > 1 indicates antagonism. Efficacy index (EI) was also calculated. Assays of efflux pump ATPase activities were conducted using a colorimetric method.

Results: This study evaluated the anticancer and antibacterial efficacy of PTM regimens that included phytopolyphenols (specifically curcumin (C) and green tea polyphenols (G)), repurposed drugs (memantine (Mem), thioridazine (TRZ), cisplatin (Cis), and 5-fluorouracil (5FU)), and ZnSO₄ (Zn) across three cultured cancer cell lines and four cultured pathogens. The most effective regimens, GC•Mem•Zn and GC•TRZ•Zn, significantly enhanced the anticancer efficacy (EI) of cisplatin across the three cancer lines (OECM-1, A549 and DLD-1) by 7, 11 and 21; 7, 9, and 17 fold, respectively, while the enhancements for 5-fluorouracil were 5, 6 and 12; 5, 5 and 9 fold, respectively. Furthermore, these PTM regimens demonstrated substantial synergistic inhibition of Na⁺-K⁺-Mg²⁺-ATPase and Mg²⁺-ATPase in the cultured cancer cells, as well as a reduction in biofilm formation by the four cultured pathogens, suggesting their potential to address the challenges of multidrug resistance in cancers and infectious diseases.

Conclusion: Given that all drugs incorporated in the PTM regimens have been clinically validated for safety and efficacy, particularly regarding their synergistic selective anticancer efficacy, inhibition of efflux pump ATPase, and antibiofilm formation of pathogens, these regimens may offer a promising therapeutic strategy to alleviate the severe side effects and drug resistance typically associated with chemotherapeutic agents. Further preclinical and clinical investigations are warranted.