Tautomycin

Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer

The androgen receptor (AR) plays an essential role in prostate cancer progression and is a key target for prostate cancer treatment. However, patients with prostate cancer undergoing androgen deprivation therapy eventually experience biochemical relapse, with hormone-sensitive prostate cancer progressing into castration-resistant prostate cancer (CRPC). The widespread application of secondary antiandrogens, such as enzalutamide, indicates that targeting AR remains the most efficient method for CRPC treatment. Unfortunately, neither can block AR signaling thoroughly, leading to AR reactivation within several months. Here, we report an approach for suppressing reactivated AR signaling in the CRPC stage. A combination of the protein phosphatase 1 subunit α (PP1α)-specific inhibitor tautomycin and enzalutamide synergistically inhibited cell proliferation and AR signaling in LNCaP and C4-2 cells, as well as in AR variant-positive 22RV1 cells. Our results revealed that enzalutamide competed with residual androgens in CRPC, enhancing tautomycin-mediated AR degradation. In addition, the remaining competitive inhibitory role of enzalutamide on AR facilitated tautomycin-induced AR degradation in 22RV1 cells, further decreasing ARv7 levels via a full-length AR/ARv7 interaction. Taken together, our findings suggest that the combination of tautomycin and enzalutamide could achieve a more comprehensive inhibition of AR signaling in CRPC. AR degraders combined with AR antagonists may represent a new therapeutic strategy for CRPC.

Tautomycin's interactions with protein phosphatase 1

It has been a long journey since tautomycin (TTM) was isolated in 1987 and the discovery that it inhibited protein phosphatase 1 (PP1) more strongly than PP2A until finally the cocrystal structure of TTM and PP1 was presented early in 2009. The fact that TTM shows preference to inhibit PP1 over PP2A makes this compound unique among the known PP1 and PP2A inhibitors. A number of groups were involved in work aiming to unravel TTM's interactions with PP1 and by doing so hoping to disentangle the secrets as to why TTM is a better inhibitor of PP1 than PP2A. This Focus Review looks back at the work conducted with TTM in order to establish its point of interaction with PP1 prior to X-ray structure. Finally the conclusions before the X-ray structure are compared with the real situation.

Tautomycin: an inhibitor of protein phosphatases 1 and 2A but not a tumor promoter on mouse skin and in rat glandular stomach

Tautomycin isolated from Streptomyces spiroverticillatus is an inhibitor of protein phosphatases 1 and 2A. Tautomycin induced hyperphosphorylation of cytokeratin peptides in human keratinocytes (PHK 16-I cells) 30 times less strongly than did okadaic acid. Repeated applications of tautomycin (30 micrograms, 40 nmol/application) did not induce tumor promotion in a two-stage carcinogenesis experiment on mouse skin initiated with 7,12-dimethylbenz[a]anthracene, whereas okadaic acid (1 microgram, 1.2 nmol/application) as a control induced tumor promotion strongly. As for mucosa of rat glandular stomach, tautomycin induced ornithine decarboxylase 4 h after intubation into the stomach. The tumor-promoting activity of tautomycin was next studied in the glandular stomach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Administration of tautomycin in the diet (1 mg rat-1 day-1), from week 9 to week 52 of the experiment, inhibited rather than enhanced tumor development in the glandular stomach initiated with MNNG. The percentages of tumor-bearing rats of the groups treated with MNNG plus tautomycin, MNNG alone, and tautomycin alone were 20.0%, 40.6%, and 0% respectively in week 52. The reason for the absence of tumor-promoting activity of tautomycin was studied in relation to tumor necrosis factor alpha (TNF alpha), an endogenous tumor promoter. We found that tautomycin neither enhanced TNF alpha mRNA expression in mouse skin nor induced TNF alpha release in a human stomach cancer cell line (KATO III cells), whereas okadaic acid did both. These results indicate that not all inhibitors of protein phosphatases are tumor promoters, and suggest that tumor promotion of the okadaic acid class of compounds is mediated by TNF alpha.

Natural products with maleic anhydride structure: nonadrides, tautomycin, chaetomellic anhydride, and other compounds

Antifungal activity of tautomycin and related compounds against Sclerotinia sclerotiorum

The potential of tautomycin to control oilseed rape stem rot was investigated in this paper. Tautomycin produced by Streptomyces spiroverticillatus strongly inhibited Sclerotinia sclerotiorum, which causes oilseed rape stem rot. Tautomycin showed great inhibition of the mycelial growth of S. sclerotiorum on potato dextrose agar (PDA) plates. The values of EC(50) and MIC were 3.26 × 10(-4) mM and 6.52 × 10(-4) mM, respectively. Tautomycin treatment also resulted in morphological abnormalities of S. sclerotiorum such as hyphal swellings and abnormally branched shapes, which were observed microscopically. Sclerotia of S. sclerotiorum soaked in the tautomycin solution for 24 h remained viable, but their ability to undergo myceliogenic germination on PDA plates was completely inhibited when the concentration of tautomycin reached 6.52 × 10(-4) mM. Tautomycin-treated oilseed rape leaves were found to have a low incidence of leaf blight caused by S. sclerotiorum. The activity of the protein phosphatase (PP) in S. sclerotiorum decreased by 41.6% and 52.6% when treated with 3.30 × 10(-4) mM and 6.52 × 10(-4) mM tautomycin, respectively. Cellular constituents also leaked from S. sclerotiorum cells incubated with tautomycin. The results suggest that the antimicrobial activity of tautomycin is due to the inhibition of the PP and then a change of membrane permeability. This paper also investigated related compounds that possess either a maleic anhydride or maleic acid moiety. Results showed 2,3-dimethylmaleic anhydride, diphenylmaleic anhydride and dimethyl maleate demonstrated significant activity against S. sclerotiorum. The values of EC(50) for these three compounds were 0.31 mM, 0.15 mM and 3.99 mM, respectively. The MIC values obtained for these compounds were 1.11 mM, 0.56 mM and 9.58 mM, respectively.