Herbimycin A

Herbimycin A is an antibiotic and protein tyrosine kinase inhibitor. Herbimycin A directly inhibits the autophosphorylation of p210 BCR-ABL with an IC₅₀ of approximately 5 μM, and reduces Src kinase activity. Herbimycin A also induces the degradation of receptor tyrosine kinases such as insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) and epidermal growth factor receptor (EGFR) via the ubiquitin-20S proteasome pathway. Herbimycin A directly modifies NF-κB p50, with the main target site involving Cys62, thereby blocking the DNA binding of p50 and NF-κB-driven gene expression. Herbimycin A can be used in studies related to tyrosine kinase signaling, chronic myeloid leukemia, NF-κB signaling, osteoclast function, apoptosis and cellular stress^{[1][2][3][4][5][6][7][8][9][10]}.
In Vitro:Herbimycin A (10-100 μM; 2 h) directly inhibits the binding of recombinant human NF-κB p50 to the NF-κB consensus DNA sequence, whereas the Cys62→Ser mutant (C62S) is insensitive to Herbimycin A at the tested concentrations, supporting that Herbimycin A inhibits NF-κB DNA binding via modifying p50 Cys62^[3].
Herbimycin A (2 μM; 1 h pre-incubation) inhibits IL-1α- or PMA-induced IL-2 production in EL4.NOB-1 cells, reducing IL-1α-induced IL-2 levels from 0.9 ng/mL to <0.1 ng/mL, and decreasing PMA-induced IL-2 levels from 50 ng/mL to 3.25 ng/mL^[3].
Herbimycin A (24 h) inhibits insulin-induced tyrosine phosphorylation of IGF-IR, IRS-1 and GAP in serum-starved MCF-7 cells in a dose-dependent manner, and its activity is detectable at a concentration of 17.4 nM after 24 h of pre-incubation^[1].
Herbimycin A (0.1-10 μg/mL; 24 h) reduces IGF-IR levels in MCF-7 cells and IR and EGFR levels in MDA-MB-468 cells in a concentration-dependent manner; in MCF-7 cells, Herbimycin A (5 μg/mL) shortens the apparent half-life of IGF-IR from >24 h to approximately 6-7 h, and its degradation can be blocked by 20S proteasome inhibitors^[1].
Herbimycin A (up to 1 μg/mL; 16-24 h) reduces foci of Rous sarcoma virus-transformed chicken embryo fibroblasts in a concentration-dependent manner, with complete disappearance of transformed foci at 1 μg/mL; the foci can reappear after the removal of Herbimycin A. It reverses transformation driven by tyrosine kinase oncogenes such as src, yes, fps, ros, abl and erbB, but exerts no similar effect on transformation driven by ras and myc^[5].
Herbimycin A (50 nM; 1-3 h) rapidly reduces the tyrosine phosphorylation levels of p210 BCR-ABL and cellular proteins in K562 cells, with approximately 55% reduction in p210 BCR-ABL phosphorylation at 1 h, and tyrosine phosphorylation signals become almost undetectable after 3 h; Herbimycin A also induces erythroid differentiation of K562 cells in a concentration-dependent manner^[2].
Herbimycin A (4 d) inhibits the growth of K562 cells with an IC₅₀ of 95 nM; its erythroid differentiation-inducing effect reaches the maximum at 1 × 10^-7 M^[2].
Herbimycin A (1 μg/mL; 2 h) upregulates the expression of multiple stress proteins in rat embryonic fibroblasts; pre-exposure to Herbimycin A for 2 h followed by an 8 h recovery period enables REF cells to acquire a thermotolerant phenotype and enhances their viability after severe heat stress at 45°C for 45 min^[7].
Herbimycin A (1-100 ng/mL) inhibits osteoclastic bone resorption in mouse bone marrow cultures, isolated rat osteoclasts and fetal mouse long bone organ cultures in a concentration-dependent manner; treatment with 100 ng/mL for 24 h also significantly reduces PTH-stimulated pp60c-Src tyrosine kinase activity in mouse bone marrow cells^[4].
Herbimycin A (1 μg/mL; 6 h) increases the expression level of the 70-kDa HSP70 to approximately 30 times that of untreated cells, and the induced HSP70 is mainly distributed in the cytoplasm^[8].
Herbimycin A inhibits p210 BCR-ABL autophosphorylation in a concentration-dependent manner in cell-free immune complex kinase assays, with an IC₅₀ of approximately 5 μM; the inhibition persists after washing away free Herbimycin A prior to the kinase reaction, supporting its direct action on p210 BCR-ABL^[6].
Herbimycin A induces HSP70 in a time- and concentration-dependent manner in A431 human epidermoid carcinoma cells^[8]. In Vivo:Herbimycin A (10 μg/mouse/injection; s.c.; 4 times/day, i.e., 40 μg/mouse/day) significantly inhibits rhIL-1α (0.1 μg/mouse/injection; s.c.; 4 times/day)-induced hypercalcemia in ICR Swiss mice; no significant effects on survival, food intake, body weight and behavior are observed at the dose of 40 μg/mouse/day^[4].
Herbimycin A (100 μg/mouse/injection; i.p.; 2 times/day; 8 d, i.e., 200 μg/mouse/day) begins to reduce blood Ca²⁺ levels on day 4 in hypercalcemic nude mice bearing human squamous cell carcinoma MH-85, with a significant reduction observed on day 8, but does not affect MH-85 tumor growth^[4].
Herbimycin A (2 mL/kg of 1 mg/6 mL solution; i.p.; single administration) induces HSP70 in the liver of male Sprague-Dawley rats, with its expression peaking at 12 h post-administration. When rats are exposed to heat stress at 45°C for 25 min after 12 h, the peak core body temperature of the Herbimycin A group is 41.16°C, which is lower than that of the vehicle group (41.76°C) and the saline group (41.85°C). Additionally, Herbimycin A significantly reduces TUNEL-positive hepatocyte apoptosis and caspase-3 activation^[10].