ABSTRACT
The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.
ABSTRACT
The androgen receptor (AR) is an important therapeutic target for all clinical states of prostate cancer. We screened cultured broths of microorganisms for their ability to suppress androgen-dependent growth of human prostate cancer LNCaP and VCaP cells without cytotoxicity. We have already identified androprostamine A (APA) from a Streptomyces culture broth as a functional inhibitor of AR. APA repressed R1881 (the synthetic androgen methyltrienolone)-induced androgen-regulated gene expression and dramatically inhibited R1881-induced prostate-specific antigen levels. However, APA did not act as an AR antagonist and did not inhibit AR transcriptional activity. Moreover, AS2405, an APA derivative, significantly inhibited the growth of VCaP cells in SCID mice upon oral administration.
Subject(s)
Antineoplastic Agents/therapeutic use , Cinnamates/therapeutic use , Oligopeptides/therapeutic use , Prostatic Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cinnamates/chemistry , Cinnamates/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Molecular Structure , Oligopeptides/chemistry , Oligopeptides/metabolism , Streptomyces/metabolismABSTRACT
Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.
Subject(s)
Antimicrobial Cationic Peptides/pharmacology , Insulin-Like Growth Factor I/metabolism , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Prostatic Neoplasms/drug therapy , Stromal Cells/drug effects , Animals , Antimicrobial Cationic Peptides/therapeutic use , Cell Line, Tumor , Coculture Techniques , Female , Humans , Male , Mice , Mitochondria/drug effects , Mitochondria/enzymology , Mitochondrial Proton-Translocating ATPases/metabolism , Molecular Docking Simulation , Prostate/cytology , Prostate/drug effects , Prostate/pathology , Prostatic Neoplasms/pathology , Stromal Cells/metabolism , Stromal Cells/pathology , Xenograft Model Antitumor AssaysABSTRACT
Intervenolin analogs with a phenyl substituent at the 2- or 3-position were synthesized. The compounds (3-11) showed weak or no inhibitory activity toward the growth of MKN-74 gastric adenocarcinoma cells, even in the presence or absence of the corresponding Hs738 stromal cells, whereas 2-substituted analogs exhibited selective anti-Helicobacter pylori activity. Introduction of a pendant side chain on the nitrogen alleviated their acute toxicity in mice. The 2-phenyl-substituted analogs are reasonable structural templates for structure-activity relationship studies toward the development of anti-H. pylori agents that do not affect human cells.The Journal of Antibiotics advance online publication, 11 October 2017; doi:10.1038/ja.2017.123.
ABSTRACT
Total synthesis of leucinostatinâ A, a modulator of tumor-stroma interactions, using asymmetric catalyses, a nitroaldol reaction, thioamide-aldol reaction, Strecker-type reaction, and alcoholysis of 3-methylglutaric anhydride, is described. We demonstrated the applicability of the established catalytic asymmetric processes to the synthesis of molecules with a complex structure. Careful analysis of the NMR data, HPLC profiles, and biological activity revealed that the correct structure of leucinostatinâ A is the epimeric form of the reported structure; the secondary alcohol within the AHMOD residue has an R configuration.
Subject(s)
Peptides/chemical synthesis , Aldehydes/chemistry , Antimicrobial Cationic Peptides , Catalysis , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/chemistry , Humans , Magnetic Resonance Spectroscopy , Peptides/chemistry , Peptides/toxicity , Stereoisomerism , Thioamides/chemistryABSTRACT
Syntheses of androprostamine A (1), and resormycin (3), anti-prostate cancer peptidyl natural products produced by microorganisms, were completed. The characteristic enamide structures of these compounds were installed using the Horner-Wadsworth-Emmons reaction from the corresponding phosphonates in reasonable Z-selectivity.
Subject(s)
Cinnamates/chemical synthesis , Oligopeptides/chemical synthesis , Propionates/chemical synthesis , Cinnamates/chemistry , Molecular Structure , Oligopeptides/chemistry , Propionates/chemistry , StereoisomerismABSTRACT
The total synthesis of NBRI16716B (2), a naturally occurring modulator of tumor-stroma interactions, was successfully achieved. Using this synthetic route, a dehydroxy analogue (21) and a derivative lacking the 5-hydroxy-3-methylpentenoyl side chain (22) became accessible. A preliminary structure-activity relationship study to unveil the structural requirements for selective inhibition of tumor cells cocultured with stromal cells revealed that both of the hydroxamate structures of 2 are indispensable, whereas the 5-hydroxy-3-methylpentenoyl side chain is not essential.
