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  • 丝裂霉素 C Conclusions br The altered intracellular

    2020-08-10

    4. Conclusions
    The altered intracellular and extracellular free l-amino 丝裂霉素 C pro-files determined in MCF-7 breast cancer cells, demonstrate the metabolic differences between the breast cancer cells and non-tumorigenic breast cells. Significantly high intracellular l-amino
    acids levels may contribute to the elevated levels of l-amino acids that are observed in the saliva and plasma of breast cancer patients. Our data indicate that cellular uptake and release of specific d-amino acids occur during cancer cell proliferation. It is clear that d-amino acids also have altered profiles in cancer cells. Specific d-amino acids showed significantly altered levels in cancer cells compared to non-tumorigenic cells. In particular, two d-amino acids, d-Ser and d-Asp, had elevated levels and could be poten-tial oncometabolites for breast cancer via selective accumulation in MCF-7 breast cancer cells. Elevated levels of d-Ser and d-Asp in MCF-7 breast cancer cells may result from upregulated enzymatic racemases. Like specific l-amino acids, d-amino acids may also be able to serve as exchange currency to drive the uptake of essen-tial and/or low abundance nonessential amino acids required by the cancer cells. A simple index using specific l- and d-amino acid relative levels has been derived and used to produce malignancy indicator (MI) of cancer. High MIs (>60) result from the increased demands of specific essential amino acids (i.e., l-Leu, l-Ile, l-Val, and l-Phe) and l-Gln which functioning like “essential” amino acids for cancer cells during proliferation. Very low MIs (<1) result from the increased demands of specific d-amino acids (i.e., d-Ser, d-Asp) or the cellular release of amino acid exchange currency (i.e., l- and d-Asn) to promote cancer cell proliferation. Such a simple and fast technique based on both high and low MI values may be used to predict/estimate the development of malignancy and perhaps in the future, early diagnosis of breast cancer. Though we have yet to explore this, it is conceivable that different cancers will each have a unique combination of MIs for a specific set of AAs, something akin to a fingerprint, which could be used for broad range cancer detection.
    Conflict of interest
    The authors declared no conflict of interest.
    Acknowledgments
    AZYP, LLC, is acknowledged for assistance and technical support for HPLC chiral column technology. We would also like to thank the Shimadzu Center for Advanced Analytical Chemistry for the use of the Shimadzu instrument (LCMS-8040). This work was supported by the Robert A. Welch Foundation (Y0026) for DWA and (Y-1933-20170325) for FMM.
    Appendix A. Supplementary data
    References
    [4] S.I. Deutsch, A.H. Tang, J.A. Burket, A.D. Benson, NMDA receptors on the surface of cancer cells: target for chemotherapy? Biomed. Pharmacother. 68
    [13] F. Cheng, Z. Wang, Y. Huang, Y. Duan, X. Wang, Investigation of salivary free amino acid profile for early diagnosis of breast cancer with ultra performance liquid chromatography-mass spectrometry, Clin. Chim. Acta 447 (Supplement C) (2015) 23–31.
    [18] V. Vinci, S.R. Parekh, Handbook of Industrial Cell Culture: Mammalian, Microbial, and Plant Cells, Humana Press, Totowa, N.J, 2003.
    [20] Oliver D. Maddocks, Christiaan F. Labuschagne, Peter D. Adams, Karen H. Vousden, Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells, Mol. Cell 61 (2) (2016) 210–221.
    [24] H. Wolosker, A. D’Aniello, S.H. Snyder, D-aspartate disposition in neuronal and endocrine tissues: ontogeny, biosynthesis and release, Neuroscience 100
    Contents lists available at ScienceDirect
    Bioorganic Chemistry
    journal homepage: www.elsevier.com/locate/bioorg
    Amide-tethered quinoline-resorcinol conjugates as a new class of HSP90 inhibitors suppressing the growth of prostate cancer cells 
    T
    Kunal Nepalia,1, Mei-Hsiang Lina,1, Min-Wu Chaob, Sheng-Jhih Penga, Kai-Cheng Hsub,d, Tony Eight Linb, Mei-Chuan Chenc, Mei-Jung Laid, Shiow-Lin Panb,d, Jing-Ping Lioua,c,d,e, a School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan b The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan c Ph.D. Program in Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taiwan d TMU Biomedical Commercialization Center, Taiwan e School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
    Keywords:
    Quinoline
    Resorcinol
    Chaperone
    Cancer
    Apoptosis
    Heat shock protein 
    The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined.