-
Manabu Kawada, Hiroyuki Inoue,
Shun-Ichi Ohba,
Masaki Hatano,
Masahide Amemiya,
Chigusa Hayashi,
Ihomi Usami,
Hikaru Abe,
Takumi Watanabe,
Naoko Kinoshita,
Masayuki Igarashi,
Tohru Masuda,
Daishiro Ikeda,
Akio Nomoto
[show abstract]
[hide abstract]
ABSTRACT: Because stromal cells can regulate the growth and metastasis of tumor cells, a compound that modulates the interaction between the stromal cells and the tumor cells can control the tumor progression. In the course of our screening for such a compound, we have isolated a new compound, intervenolin, from the culture broth of Nocardia sp. ML96-86F2. Intervenolin inhibits the growth of human gastric and colorectal cancer cell lines in the coculture with the respective organ-derived stromal cells more strongly than that of the cancer cells cultured alone. Intervenolin shows antitumor effect against a xenograft model of human colorectal cancer cells in vivo. Furthermore, intervenolin exerts selective anti-Helicobacter pylori effect.The Journal of Antibiotics advance online publication, 1 May 2013; doi:10.1038/ja.2013.42.
The Journal of Antibiotics 05/2013; · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Synthesis of intervenolin, a natural quinolone discovered by screening for selective growth inhibitors of cancer cells cocultured with stromal cells over monocultured cells, was achieved. The synthesis utilized a thiocyanate-isothiocyanate rearrangement and Suzuki-Miyaura coupling to furnish the characteristic substituents, the iminodithiocarbonate moiety, and the geranyl side chain, respectively. In vivo studies showed that intervenolin inhibited tumor tissue growth in model mice.
Organic Letters 04/2013; · 5.86 Impact Factor
-
The Journal of Antibiotics 10/2010; 63(10):611-3. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prostate stroma can regulate the growth and metastasis of prostate cancer through the tumor-stromal cell interactions. Thus, small molecules that modulate the tumor-stromal cell interactions will have a chance to become new antitumor drugs. In the course of our screening of the modulators, we isolated three new natural compounds, NBRI16716A (1), NBRI16716B (2) and NBRI16716C (3), from the fermentation broth of Perisporiopsis melioloides Mer-f16716, although compound 2 was already reported as a chemical degradation product of isotriornicin. Compounds 1 and 2 inhibited the growth of human prostate cancer DU-145 cells in the coculture with human prostate stromal cells (PrSCs) more strongly than that of DU-145 cells alone. Furthermore, both compounds showed antitumor effect against xenograft models of DU-145 cells and PrSCs in vivo.
The Journal of Antibiotics 06/2010; 63(6):319-23. · 1.65 Impact Factor
-
Manabu Kawada,
Ihomi Usami,
Tetsuya Someno,
Takumi Watanabe,
Hikaru Abe, Hiroyuki Inoue,
Shun-ichi Ohba,
Tohru Masuda,
Yuji Tabata,
Sho-ichi Yamaguchi,
Daishiro Ikeda
[show abstract]
[hide abstract]
ABSTRACT: The interaction between the receptor for advanced glycation end-product (RAGE) and amphoterin has an important role in tumor growth and metastasis. Because the abrogation of the interaction results in the inhibition of the tumor growth and metastasis, we designed a screening system for an inhibitor of the interaction between RAGE and amphoterin. In the course of our screening of the inhibitor, we isolated a novel natural compound NBRI17671 (1) from the fermentation broth of Acremonium sp. CR17671. We also modified 1 into a more active NBRI17671al (2). Although 1 at 50 g ml(-1) weakly inhibited binding of various cells to amphoterin, 2 at 50 g ml(-1) inhibited it by >50% of control. Compound 2 effectively inhibited the tumor growth of glioma and lung tumor xenografts in mice at 25 mg kg(-1). Furthermore, 2 was found to downregulate mitogen-activated protein kinase (MAPK) activity in the tumor cells.
The Journal of Antibiotics 04/2010; 63(5):237-43. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although cytostatin analog protein phosphatase 2A (PP2A)-specific inhibitors are promising candidates of a new type of anticancer drug, their development has been hindered because of their liability. To find new classes of PP2A-specific inhibitors, we conducted a screening with microbial metabolites and found that rubratoxin A, a classical mycotoxin, is a highly specific and potent inhibitor of the enzyme. While rubratoxin A inhibits PP2A at Ki = 28.7 nm, it hardly inhibited any other phosphatases examined. Rubratoxin B, a close analog, also specifically but weakly inhibits PP2A at Ki = 3.1 microM. The inhibition of intracellular PP2A in cultured cells is obviously observed with 20 microM rubratoxin A treatment for 3 h, inducing the overphosphorylation in PP2A substrate proteins. Although rubratoxins and cytostatin differ in the apparent structures, these compounds share similarities in the structures in detail and PP2A-binding manners. Rubratoxin A showed higher suppression of tumor metastasis and reduction of the primary tumor volume than cytostatin in mouse experiments. As a successor of cytostatin analogs, rubratoxin A should be a good compound leading to the development of antitumor drugs targeting PP2A.
Cancer Science 11/2009; 101(3):743-50. · 3.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developed in vitro coculture system, in which the growth of human prostate cancer DU-145 cells is stimulated by prostate stromal cells (PrSC) through insulin-like growth factor I (IGF-I). Using this system, we have been searching for small molecules that inhibit tumor growth through modulation of tumor-stromal cell interactions. As a result, we have found that leucinostatins and atpenins, natural antifungal antibiotics, inhibit the growth of DU-145 cells cocultured with PrSC more strongly than that of DU-145 cells alone. In this study we examined the antitumor effects of these small molecules in vitro and in vivo. When DU-145 cells were coinoculated with PrSC subcutaneously in nude mice, leucinostatin A was found to significantly suppress the tumor growth more than atpenin B. The antitumor effect of leucinostatin A in vivo was not obtained against the tumors of DU-145 cells alone. RT-PCR experiments revealed that leucinostatin A specifically inhibited IGF-I expression in PrSC without effect on expressions of other IGF axis molecules. Leucinostatins and atpenins are known to abrogate mitochondrial functions. However, when we used mitochondrial DNA-depleted, pseudo-rho(0) cells, we found that one of leucinostain A actions certainly depended on mitochondrial function, but it actually inhibited the growth of DU-145 cells more strongly in coculture with pseudo-rho(0) PrSC and reduced IGF-I expression in pseudo-rho(0) PrSC. Taken together, our results suggested that leucinostatin A inhibited prostate cancer cell growth through reduction of IGF-I expression in PrSC.
International Journal of Cancer 09/2009; 126(4):810-8. · 5.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Decrease of ceramide in the skin is one of the aggravating factors of atopic dermatitis. The skin is often infected by ceramidase-producing bacteria, such as Pseudomonas aeruginosa. The bacterial ceramidase then degrades ceramide in the skin. To develop anti-atopic dermatitis drugs, we searched for ceramidase inhibitors, which led to the discovery of ceramidastin, a novel inhibitor of bacterial ceramidase, from the culture broth of Penicillium sp. Mer-f17067. Ceramidastin inhibited the bacterial ceramidase with an IC(50) value of 6.25 microg ml(-1). Here we describe the isolation, physicochemical properties, structure determination and biological activity of ceramidastin.
The Journal of Antibiotics 02/2009; 62(2):63-7. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Because stroma in tumor tissues can promote prostate cancer development, modulation of tumor-stromal cell interactions may represent an attractive new strategy for cancer treatment. Here, we report that phthoxazolin A and its analog inthomycin B inhibit the growth of human prostate cancer DU-145 cells by modulating tumor-stromal cell interactions. Using an in vitro coculture system, in which prostate cancer cell growth is upregulated by prostate stromal cells (PrSC), we found that phthoxazolin A and inthomycin B strongly inhibited the growth of DU-145 cells when in coculture with PrSC compared to DU-145 cells cultured alone. Although PrSC consist of both fibroblasts and myofibroblasts, phthoxazolin A and inthomycin B inhibited the expression of smooth muscle alpha-actin, a myofibroblast marker, without affecting vimentin and beta-actin expression. Because myofibroblasts secrete various factors that can promote tumor cell growth, we examined whether the inhibitory compounds affected the secretion of such factors from PrSC. Proteomic analysis and reverse transcription-polymerase chain reaction revealed that phthoxazolin A and inthomycin B inhibited the expression of several insulin-like growth factor binding proteins and insulin-like growth factor (IGF)-I by PrSC. Transforming growth factor-beta1 increased myofibroblast numbers and IGF-I levels in PrSC. Phthoxazolin A inhibited transforming growth factor-beta1 activity without altering phosphorylation of the downstream molecule smad2. Furthermore, conditioned medium from phthoxazolin A-treated PrSC failed to increase the phosphorylation of IGF-IR and Akt in DU-145 cells. Taken together, our results suggested that phthoxazolin A acts as a small-molecule modulator of tumor-stromal cell interactions that can indirectly suppress prostate cancer cell growth through inhibition of IGF-I production by PrSC.
Cancer Science 11/2008; 100(1):150-7. · 3.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have recently established a highly tumorigenic cell line, LNCaP-CR, derived from human androgen-dependent prostate cancer LNCaP cells. In the present study, we examined the genes responsible for the high tumorigenicity of LNCaP-CR cells. The cDNA microarray analysis and protein array of secreted factors indicated angiogenin (ANG), an angiogenic factor, as a candidate gene. Reverse transcription-polymerase chain reaction and immunoassay confirmed that LNCaP-CR cells expressed high levels of ANG but not vascular endothelial growth factor (VEGF), compared with the parental LNCaP cells. We also proved that another tumorigenic androgen receptor-positive prostate cancer cell line, 22Rv1, secretes higher levels of ANG than VEGF. To assess the contribution of ANG to the highly tumorigenic phenotype, we transfected the ANG gene into LNCaP cells in order to overexpress ANG, and also transfected ANG small interfering RNA-expressing constructs into LNCaP-CR cells to downregulate ANG. Overexpression of ANG in LNCaP cells did not affect their growth in vitro, but it significantly enhanced tumorigenicity and angiogenesis in vivo. In contrast, knockdown of ANG expression in LNCaP-CR cells also did not affect the growth in vitro, but it led to a significant decrease in tumorigenicity and angiogenesis. Taken together, ANG is one of the genes responsible for the high tumorigenicity of LNCaP-CR cells. Thus, our results support the idea that ANG is an attractive target for cancer therapy and show that LNCaP-CR cells are useful for studying ANG action and experimental therapeutic approaches targeting ANG.
Cancer Science 04/2007; 98(3):350-6. · 3.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Human androgen-dependent prostate cancer LNCaP cells are low tumorigenic even in immunodeficient mice and were killed by the synergistic effect of inflammatory cytokines, IL-beta and IL-6. To establish a highly tumorigenic LNCaP cell line, we isolated the cytokine-resistant LNCaP-CR cell line and examined the phenotypes. The parental LNCaP cells were induced to commit apoptosis by the addition of IL-1beta and IL-6, but LNCaP-CR cells showed strong resistance against the cytokine action. However, LNCaP-CR cells did not exhibit any resistance to various antitumor drugs investigated. While LNCaP cells formed only palpable tumors in SCID mice, LNCaP-CR cells readily made tumors and their growth was significantly higher than that of LNCaP cells. Moreover, LNCaP tumor-bearing mice gained the weight gradually, but LNCaP-CR tumor-bearing mice significantly lost their body weight. LNCaP-CR cells still responded to androgen action and expressed AR, erbB2, IL-1R, IL-6R, gp130, STAT3, p21, Bcl-2 and caspase-3 as well as LNCaP cells. These results indicate that LNCaP-CR cell line is a new type of tumorigenic LNCaP cell lines and should be useful for identifying responsible genes of tumorigenicity, cytokine resistance, and also cachexia.
Cancer Letters 11/2006; 242(1):46-52. · 4.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Kigamicin D did not show any immunosuppressive activity in mixed lymphocyte culture reaction and mitogen induced lymphocyte blastogenesis in vitro and graft versus host reaction in vivo. Natural killer cell activity in spleen cells was not affected by oral administration of kigamicin D. Instead, delayed-type hypersensitivity response to sheep red blood cells was stimulated at a broad dosage level. It is concluded that kigamicin D increases cellular immunity to specific antigen.
The Journal of Antibiotics 05/2006; 59(4):215-9. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prostate cancer shows high expression of type I insulin-like growth factor (IGF-I) receptor (IGF-IR) and prostate stromal cells (PrSC) produce IGF-I. Although high plasma level of IGF-I is a risk factor of prostate cancer, the significance of the prostate stromal IGF-I in the regulation of prostate cancer remains elusive. Here we show that the stromal IGF-I certainly regulates the development of prostate cancer. Coinoculation of PrSC increased the growth of human prostate cancer LNCaP and DU-145 tumors in severe combined immunodeficient mice. The conditioned medium of PrSC, as well as IGF-I, induced phosphorylation of IGF-IR and increased the growth of LNCaP and DU-145 cells. PrSC, but not LNCaP and DU-145 cells, secreted significant amounts of IGF-I. Coculture with PrSC increased the growth of DU-145 cells in vitro but the pretreatment of PrSC with small interfering RNA of IGF-I did not enhance it. Furthermore, various chemical inhibitors consisting of 79 compounds with approximately 60 different targets led to the finding that only IGF-IR inhibitor suppressed the PrSC-induced growth enhancement of DU-145 cells. Thus, these results show that the prostate stromal IGF-I mediates tumor-stromal cell interactions of prostate cancer to accelerate tumor growth, supporting the idea that the IGF-I signaling is a valuable target for the treatment of prostate cancer.
Cancer Research 05/2006; 66(8):4419-25. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Deficiency of Fas-mediated apoptosis is one of the mechanisms involved in the immune evasion by tumors. Thus, it might be a practical approach for cancer treatment that Fas-mediated apoptosis in tumor cells is modified by drugs. In the course of screening, we have isolated two new naphthoquinones, f13102A and B, from the culture broth of fungus strain F-13102. Coumpound f13102A sensitizes Fas-resistant human lung adenocarcinoma A549 cells to apoptosis.Keywords: chemotherapy, tumor immunity, naphthoquinone, Fas, CD95
The Journal of Antibiotics 08/2005; 58(9):590-593. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In the course of screening for inhibitors of osteoclastogenesis, a new substance designated as ICM0201 was isolated from a fermentation broth of Cunninghamella sp. F-1490. ICM0201 inhibited the formation of osteoclasts in mouse bone marrow cells with an IC50 value of 0.78 microg/ml and showed weak cytotoxicity against bone marrow cells.
The Journal of Antibiotics 04/2003; 56(3):209-13. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: ICM0201 (1), a new inhibitor of murine osteoclastogenesis in culture was isolated from a fermentation broth of Cunninghamella sp. F-1490. The structure of ICM0201 was determined to be (3S,10aR)-3,4a-dihydroxy-2,3,4,4a-tetrahydro-2H-pyrano[3,2-b]benzo[e]morpholine-9-carboxylic acid by spectroscopic analyses and chemical studies. The structure of 1 is unique in that the tricycle ring system is composed of aminal and hemiacetal bonds.
The Journal of Antibiotics 04/2003; 56(3):214-8. · 1.65 Impact Factor
