Herbal formula enhances 5-fluorouracil activity through suppression of thymidylate synthase

Traditional Chinese herbal medicine(TCM)has been shown to enhance the efficacy of standard anticancer agents.However,there are only a limited number of well-controlled preclinical and clinical studies documenting the potential benefit of TCM.OBJECTIVE To identify biologically active formulas that were effective against colorectal cancer(CRC)by screening TCM formulas in in vitro and in vivo animal models.METHODS Cell growth assays,cell cycle analysis,immunoblot analysis and qRT-PCR were performed to investigate the mechanism(s)of action of the formulason human CRC cells.In vivo animal models were used to evaluate the antitumor activity of formulasalone and in combination with 5-FU.RESULTS We identified Huangqin Gegen Tang(HQGGT)which suppressed the in vivo growth of human CRC HT-29 xenografts.HQGGT significantly inhibited the growth of CRC cell lines.HQGGT enhanced the cytotoxicity of 5-FU against human 5-FU-resistant cells(H630R1)and mouse colon cancer cells(MC38).This synergy was the result of suppression of thymidylate synthase expression by HQGGT.HQGGT significantly enhanced the antitumor effect of 5-FU in mice bearing MC38 xenografts.Ongoing studies have identified Huangqin as the herb responsible for TS inhibi⁃tion.CONCLUSION These findings provide support for the potential role of HQGGT as a novel modulator of fluoropyrim⁃idine chemotherapy for CRC treatment.

Emerging roles of Aurora-A kinase in cancer therapy resistance

Aurora kinase A(Aurora-A),a serine/threonine kinase,plays a pivotal role in various cellular processes,including mitotic entry,centrosome maturation and spindle formation.Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer,including lung cancer,colorectal cancer,and breast cancer.Alteration of Aurora-A impacts multiple cancer hallmarks,especially,immortalization,energy metabolism,immune escape and cell death resistance which are involved in cancer progression and resistance.This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance,including chemoresistance(taxanes,cisplatin,cyclophosphamide),targeted therapy resistance(osimertinib,imatinib,sorafenib,etc.),endocrine therapy resistance(tamoxifen,fulvestrant) and radioresistance.Specifically,the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair,feedback activation bypass pathways,resistance to apoptosis,necroptosis and autophagy,metastasis,and stemness.Noticeably,our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1,ARID1A and MYC gene mutation tumors,and potential synergistic strategy for m TOR,PAK1,MDM2,MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase.In addition,we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.