Fostriecin sodium salt

IC50: Inhibit protein phosphatase types 2A (PP2A) and 4 (PP4) intensively with an IC50 of 1.5 nM and 3 nM respectively. Inhibit topoisomerase II (Topo II) and protein phosphatase type 1 (PP1) slightly with an IC50 of 40 μM and 131 μM respectively.

Fostriecin, an anti-tumor antibiotic originates from Streptomyces pulveraceus, is considered to exert its activity by interfering the reversible phosphorylation of several important proteins in cell cycle. Fostriecin sodium salt also exhibits anti-tumor activity via suppressing enzymes including PP2A, PP4, PP1 and Topo II. [1]

In vitro: A human tumor cloning assay was adopted to investigate the antineoplastic activity of fostriecin. Variety of histologic tumor cells exposure to 10 mg/ml fostriecin resulted in 27% in vitro anticancer response. In another study using HeLa cells, by suppressing the Topo II catalytic activity, 0.22 mM fostriecin could lead to more than 90% inhibition of cancer cell DNA synthesis. [2,3]

In vivo: Fostriecin showed intensively cytotoxicity against a number of cancer cell lines and had a strong antitumor effect in animals. 10 mg/ml fostriecin could substantially suppress P388 and L1210 leukemias in mice. [2,3]

Clinical trial: Fostriecin reached clinical phase I study sponsored by the National Cancer Institute to investigate its antitumor activity in human. With dosages escalated from 2 to 20 mg/m2/day, fostriecin was administered as a 60-min intravenous (IV) infusion to 20 patients in cancer for 5 days. Although the trials were suspended due to the concerns about the storage stability of this naturally originated compound, this discovery ignited a broad interest in derivatives of fostriecin. [1,4]

References:
[1] Zhang X, Wu J, Fang L, Willis WD.  The effects of protein phosphatase inhibitors on the duration of central sensitization of rat dorsal horn neurons following injection of capsaicin. Mol Pain. 2006 Jul; 2(23). DOI:10.1186/1744-8069-2-23.
[2] Scheithauer W, Von Hoff DD, Clark G, Shillis JL, Elslager EF.  In vitro activity of the novel antitumor antibiotic fostriecin (CI-920) in a human tumor cloning assay. Eur J Cancer Res & Clin Oncol. 1986 Aug; 22(8): 921-6.
[3] Gedik CM, Collins AR.  Comparison of effects of fostriecin, novobiocin, and camptothecin, inhibitors of DNA topoisomerases, on DNA replication and repair in human cells. Nnucleic Acids Res. 1990 Aug; 18(4):1008-13.
[4] Le LH, Erlichman C, Pillon L, Thiessen JJ, Day A, Wainman N, Eisenhauer EA, Moore MJ.  Phase I and pharmacokinetic study of fostriecin given as an intravenous bolus daily for five consecutive days.
Invest New Drugs.  2004 Apr; 22(2):159-67.

Purification of protein phosphatase 4 catalytic subunit: inhibition by the antitumour drug fostriecin and other tumour suppressors and promoters.[Pubmed:9714542]

FEBS Lett. 1998 Jul 24;431(3):357-61.

Protein phosphatase 4 (PP4) is a protein serine/threonine phosphatase that predominantly localises to centrosomes and plays a role in microtubule organisation at centrosomes. Here, PP4 catalytic subunit has been purified from porcine testis to near homogeneity and a specific activity of 680 mU/mg against phosphorylase alpha. The antitumour drug, fostriecin, inhibits PP4 catalytic subunit (IC50 3 nM) with similar potency to PP2A catalytic subunit (IC50 1.5 nM). PP4 is also inhibited in the nanomolar range by several naturally occurring tumour promoters and toxins, with similar IC50 values to those obtained for PP2A. The gene for human PP4 catalytic subunit localises to 16p11.2.

Fostriecin, an antitumor antibiotic with inhibitory activity against serine/threonine protein phosphatases types 1 (PP1) and 2A (PP2A), is highly selective for PP2A.[Pubmed:9373158]

FEBS Lett. 1997 Oct 27;416(3):230-4.

Fostriecin, an antitumor antibiotic produced by Streptomyces pulveraceus, is a strong inhibitor of type 2A (PP2A; IC50 3.2 nM) and a weak inhibitor of type 1 (PP1; IC50 131 microM) serine/threonine protein phosphatases. Fostriecin has no apparent effect on the activity of PP2B, and dose-inhibition studies conducted with whole cell homogenates indicate that fostriecin also inhibits the native forms of PP1 and PP2A. Studies with recombinant PP1/PP2A chimeras indicate that okadaic acid and fostriecin have different binding sites.

Novel antitumor agents CI-920, PD 113,270 and PD 113,271. I. Taxonomy, fermentation and biological properties.[Pubmed:6689323]

J Antibiot (Tokyo). 1983 Dec;36(12):1595-600.

CI-920 (PD 110,161) and two analogues (PD 113,270 and PD 113,271) are novel antitumor compounds produced by a new actinomycete characterized as Streptomyces pulveraceus subsp. fostreus ATCC 31906. The antitumor compounds are predominantly produced during the stationary (idiophase) growth phase of the organism. CI-920 is active versus the murine P388 lymphocytic and L1210 lymphoid leukemia with T/C values of 246 and 207, respectively. This compound has no significant antimicrobial activity.