Screening of inhibitors for anchorage-independent tumor cell growth from microbial metabolites and their application in cancer chemotherapy

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Inhibitors for anchorage-independent growth of tumor cells were screened from microbial secondary metabolites. Five hundred strains of actinomycetes and one hundred strains of fungi were cultured in liquid medium and the 1-butanol extracts were subjected to the screening. One actinomycete and one fungus showed potent inhibitory activity against the anchorage-independent growth of human colon tumor DLD-1 cells. The active compounds were isolated from the culture broth by chromatography using HPLC analysis and bioassay.From the actinomycete, a novel antitumor compound TT2149-C was isolated. The producing-strain, was identified as Streptomyces thermoviolaceus TP-A0648 by taxonomic studies. TT2149-C is an analog of spicamycin, which was isolated from Streptomyces sp. as an antitumor antibiotic. TT2149-C inhibited the anchorage-independent growth of DLD-1 cells with the IC_<50> of 29 nM whereas it inhibited the anchorage-dependent growth with. the IC_<50> of 68 nM. TT2149-C showed very pote … More nt cytocidal activity against a variety of human cancer cell lines with the IC50 of 0.1 to 120 nM.A novel antitumor compound anicequol was isolated from the fungus Penicillium aurantiogriseum TP-F0213. The structure of anicequol was confirmed as (3β, 5α, 7β, 11β, 16β-16-acetoxy-3,7,11-trihydroxyergost-22-en-6-one by X-ray diffraction of bis-p-bromobenzoate of anicequol. Anicequol inhibited the anchorage-independent growth of DLD-1 cells with the IC_<50> of 1.2 μM whereas it inhibited the anchorage-dependent growth with the IC_<50> of 40 μM. The selectivity of anicequol is superior to that of TT2149-C. Anicequol did not show activity against protein kinases, farnesyl transferase and tublin function. Structure-activity relationship (SAR) of anicequol, was studied using synthetic derivatives. Acetylation of 3-and 7-hydroxy groups resulted in the loss of activity. However, the acetylation of 3-hydroxy group reduced the toxicity to the anchorage-dependent growth but enhanced the cytotoxicity to the anchorage-independent growth. SAR of anicequol will be studied furthermore. Less