Actinonin

Actinonin, a peptidomimetic antibiotic that inhibits enkephalin-aminopeptidase, enkephalinase A, and dipeptidylaminopeptidase with IC₅₀ values of 0.39μM, 5.6μM, and 1.1μM, respectively^[1]. Actinonin can inhibit the constitutive expression of functional recombinant MT1-MMP protein, block the activation of proMMP-2, and suppress angiogenesis^[2]. Actinonin has been widely used as an antibacterial agent to inhibit the growth of Gram-positive bacteria and difficult-to-culture Gram-negative bacteria^[3].

In vitro, Actinonin treatment for 5 days significantly inhibited the viability of HL-60 cells, NB4 cells and AKR cells with IC₅₀ values of 2µg/ml, 5µg/ml, and 3µg/ml, respectively^[4]. Treatment of U937 cells with 20μg/ml of Actinonin for 24 hours significantly induced cell apoptosis, accompanied by a significant increase in the activities of caspase-3 and caspase-7-like enzymes and extensive fragmentation of DNA^[5]. Actinonin pretreatment at 26nM for 1 hour can reduce the expression of HSP70 induced by celastrol in U937 cells, and synergistically inhibit cell proliferation with celastrol^[6].

In vivo, Actinonin treatment via daily intraperitoneal injection (150mg/kg/day) for 2 weeks significantly inhibited tumor growth in the A549 xenograft mouse model without causing any toxic reactions^[7]. Thirty minutes before the mice underwent cecal ligation and puncture (CLP), a single dose of Actinonin (20mg/kg) was injected intraperitoneally, which could reduce the serum IL-1β level and prevent the decline in renal capillary perfusion^[8].

References:
[1] Hachisu M, Hiranuma T, Murata S, et al. Analgesic effect of actinonin, a new potent inhibitor of multiple enkephalin degrading enzymes[J]. Life sciences, 1987, 41(2): 235-240.
[2] Sina A, Lord-Dufour S, Annabi B. Cell-based evidence for aminopeptidase N/CD13 inhibitor actinonin targeting of MT1-MMP-mediated proMMP-2 activation[J]. Cancer letters, 2009, 279(2): 171-176.
[3] Chen D Z, Patel D V, Hackbarth C J, et al. Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor[J]. Biochemistry, 2000, 39(6): 1256-1262.
[4] Xu Y, Lai L T, Gabrilove J L, et al. Antitumor activity of actinonin in vitro and in vivo[J]. Clinical cancer research: an official journal of the American Association for Cancer Research, 1998, 4(1): 171-176.
[5] Grujic M, Zavasnik-Bergant T, Pejler G, et al. Actinonin induces apoptosis in U937 leukemia cells[J]. Cancer letters, 2005, 223(2): 211-218.
[6] Peng B, Zhang X, Cao F, et al. Peptide deformylase inhibitor actinonin reduces celastrol’s HSP70 induction while synergizing proliferation inhibition in tumor cells[J]. Bmc Cancer, 2014, 14(1): 146.
[7] Lee M D, She Y, Soskis M J, et al. Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics[J]. The Journal of clinical investigation, 2004, 114(8): 1107-1116.
[8] Wang Z, Herzog C, Kaushal G P, et al. Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis[J]. Shock, 2011, 35(2): 141-147.