Antitumor activity of leptomycin B.

Komiyama, Kanki; Okada, Kenji; Tomisaka, Shigeru; Umezawa, Iwao; Hamamoto, Toshiro; Beppu, Teruhiko

doi:10.7164/antibiotics.38.427

Cited by 35 publications

(21 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LMB, which is an unsaturated, branched-chain fatty acid originally found as an anti-fungal substance (Hamamoto et al, 1983a, b), has also been reported to suppress cell proliferation (Komiyama et al, 1985;Yoshida et al, 1990) and a phase I trial of LMB therapy was performed in patients with malignant tumors (Newlands et al, 1996). The primary side-effects at that time were reported to be nausea and anorexia during systemic treatment (Newlands et al, 1996).…”

Section: Il-1a Into Their Active Forms (Mccawley and Matrisianmentioning

confidence: 96%

“…Thus, LMB is considered to potentially function in vivo and might exert many different biological effects. But the role of LMB in the actual metabolism of the extracellular matrix has not yet been elucidated, although it has been reported to potentially inhibit the proliferation of tumor cells (Komiyama et al, 1985;Yoshida et al, 1990). We speculated that LMB could influence the induction of MMP-9 expression, which is controlled by many gene-regulatory elements.…”

mentioning

confidence: 96%

See 1 more Smart Citation

Leptomycin B Reduces Matrix Metalloproteinase-9 Expression and Suppresses Cutaneous Inflammation

Kobayashi

Shinkai

2005

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Matrix metalloproteinase-9 (MMP-9), a type of gelatinase, plays many roles in tissue metabolism, especially in inflammation, and many regulatory elements have been reported in the promoter region of its encoding gene. Leptomycin B, which regulates the nucleo-cytoplasmic trafficking of proteins, including transcription-factor-related ones, has the potential to exert important biological effects. The addition of leptomycin B to keratinocytes in culture had no effect on matrix metalloproteinase-2 (another gelatinase) but caused the selective down-regulation of MMP-9 during the stimulation of differentiation with high Ca(2+) or transforming growth factor-beta, as well as during the stimulation of inflammation by tumor necrosis factor-alpha or interleukin-1alpha. This down-regulation depended on multiple regulatory elements in the promoter of MMP-9 including KRE-M9 (which we have recently identified), and a classical 12-o-tetradecanoyl-phorbol-13-acetate-responsive element. The topical application of leptomycin B to murine skin also effectively suppressed inflammation, including MMP-9 expression, after ultraviolet B irradiation. These results suggest that the application of leptomycin B and/or its derivatives could be useful for treating many inflammatory conditions.

show abstract

Section: Il-1a Into Their Active Forms (Mccawley and Matrisianmentioning

confidence: 96%

mentioning

confidence: 96%

Leptomycin B Reduces Matrix Metalloproteinase-9 Expression and Suppresses Cutaneous Inflammation

Kobayashi

Shinkai

2005

Journal of Investigative Dermatology

View full text Add to dashboard Cite

show abstract

“…As suggested by their rev-like leucine-rich repeats, coimmunoprecipitation experiments demonstrated that pp32 and APRIL interact with the nuclear export factor CRM1. Accordingly, inhibition of CRM1 with the antifungal and antitumor agent leptomycin B (LMB; [102][103][104]) resulted in the loss of shuttling and nuclear accumulation of pp32 and APRIL. Most important, CRM1 inhibition produced increased association of HuR with pp32 and with APRIL, and an increase in HuR's ability to bind nuclear poly(A) + RNA in vivo.…”

Section: Review Articlementioning

confidence: 99%

HuR and mRNA stability

Brennan¹,

Steitz²

2001

CMLS, Cell. Mol. Life Sci.

971

978

View full text Add to dashboard Cite

An important mechanism of posttranscriptional gene regulation in mammalian cells is the rapid degradation of messenger RNAs (mRNAs) signaled by AU-rich elements (AREs) in their 3' untranslated regions. HuR, a ubiquitously expressed member of the Hu family of RNA-binding proteins related to Drosophila ELAV, selectively binds AREs and stabilizes ARE-containing mRNAs when overexpressed in cultured cells. This review discusses mRNA decay as a general form of gene regulation, decay signaled by AREs, and the role of HuR and its Hu-family relatives in antagonizing this mRNA degradation pathway. The influence of newly identified protein ligands to HuR on HuR function in both normal and stressed cells may explain how ARE-mediated mRNA decay is regulated in response to environmental change.

show abstract

“…The ability of LMB to sensitize NIH3T3 cells to radiation-induced apoptosis suggests that this fungal metabolite may find use as an anticancer agent in conjunction with other apoptosis-inducing stimuli. LMB1 has antitumor activity against some solid tumors xenografted into mice, 35 but it has yet to be tried in vivo with radiation or chemotherapeutic drugs. Because cyclin B1 is critical in controlling the mitosis in normal cells, LMB is likely to have some toxicity in normal cells, a characteristic that LMB would share with other chemotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

Nuclear localization of cyclin B1 regulates DNA damage–induced apoptosis

Porter

Cukier

Lee

2003

Blood

View full text Add to dashboard Cite

Some cells undergo apoptosis in response to DNA damage, whereas others do not. To understand the biochemical pathways controlling this differential response, we have studied the intracellular localization of cyclin B1 in cell types sensitive or resistant to apoptosis induced by DNA damage. We found that cyclin B1 protein accumulates in the nucleus of cells that are sensitive to ␥ radiation-induced apoptosis (thymocytes, lymphoid cell lines), but remains cytoplasmic in apoptosis-resistant cells (primary and transformed fibroblasts). Treatment of both cell types with leptomycin B, an inhibitor of CRM1-dependent cyclin B1 nuclear export, induces apoptosis. Furthermore, ectopic expression of cyclin B1-5xE, a protein that preferentially localizes to the nucleus, is sufficient to trigger apoptosis. Conversely, expression of cyclin B1-5xA, a predominantly cytoplasmic protein, fails to induce apoptosis. This suggests that nuclear accumulation is necessary for cyclin B1-dependent apoptosis. Our observations are consistent with the idea that localization of cyclin B1 is among the factors determining the cellular decision to undergo apoptosis in response to DNA damage. IntroductionDNA damage causes both cell cycle arrest and apoptosis. 1 However, the response to genotoxic stress varies between tissues and some cells rapidly undergo apoptosis in response to DNA damage, whereas others do not. For example, hematopoietic cells undergo apoptosis after exposure to as little as 100 to 200 cGy ␥ radiation, 2,3 whereas fibroblastlike cells are resistant to these doses. 4,5 The biochemical basis for this difference has yet to be clearly established. In this report, we have investigated the role that the cyclin B1 cell cycle regulator has in controlling the apoptotic response to ␥ radiation. Cyclin B1 has important roles in both mitosis 6 and ␥ radiation-induced apoptosis. 7 B-type cyclins are binding partners of the cdc2 (cdk1) serine/ threonine kinase. 8 The cyclin B/cdc2 heterodimer is referred to as the M phase-promoting factor (MPF) because of its ability to induce mitosis by phosphorylating and activating enzymes regulating chromatin condensation, nuclear membrane breakdown, and mitotic microtubule reorganization. 9 Of the B-type cyclins, B1 is likely to be most important in mitotic regulation because mice lacking cyclin B2 develop normally and are fertile, whereas mice lacking cyclin B1 die during embryonic development. 10 The kinase activity of the cyclin B1/cdc2 complex is regulated by the abundance of cyclin B, the association kinetics of cyclin B and cdc2, and by the phosphorylation state of cdc2. 8 For mitosis to proceed, an active cyclin B/cdc2 complex must also accumulate in the nucleus in late prophase. 11 Nuclear accumulation of cyclin B1 at the onset of mitosis is dependent on phosphorylation within its cytoplasmic retention signal (CRS) 12,13 In Xenopus, cyclin B1 nuclear accumulation is controlled, at least in part, through phosphorylation by the pololike kinase. 14 Phosphorylation of the CRS may enhance associati...

show abstract

Antitumor activity of leptomycin B.

Abstract: Leptomycin B was first reported by HAMAMOTO et a!. as an antifungal antibiotic, and showed remarkable cytotoxicity on mammalian cells').

Cited by 35 publications

References 4 publications

Leptomycin B Reduces Matrix Metalloproteinase-9 Expression and Suppresses Cutaneous Inflammation

Leptomycin B Reduces Matrix Metalloproteinase-9 Expression and Suppresses Cutaneous Inflammation

HuR and mRNA stability

Nuclear localization of cyclin B1 regulates DNA damage–induced apoptosis

Contact Info

Product

Resources

About