Author: Erin Connelly : Posted to Decoded Science on November 20, 2011 at 8:28 am
Structure of Geldanamycin: Image by Calvero
Geldanamycin and its derivatives (17-AAG, 17-DMAG) are part of the benzoquinone ansamycin family, a class of molecules which demonstrate marked antimicrobal activity against bacteria, parasites and some viruses. These antibiotics are naturally produced by microorganisms as a defense mechanism against disease-causing invaders.
Geldanamycin was first isolated in Streptomyces hygroscopicus, a filamentous soil bacterium, in 1970 and was later identified to have strong anti-tumor qualities. Since the 1990s, research into the anti-cancer properties of geldanamycin has been ongoing. Current studies continue to reveal promising insights into the mechanism of the drug and its potential for use in a clinical setting.
Geldanamycin Mechanism
The Met Receptor
It has been shown, through research done by Vande Woude, Xie, Webb, Panaretou and others, that the met receptor is very influential in the metastasis and invasion of cancer cells. Met is normally expressed as a membrane receptor in epithelial cells where human growth factor (HGF) binds and causes signaling. This met/HGF signaling is important for a number of bodily processes, including wound healing, embryo development, and tissue repair. However, when the met receptor is abnormally expressed, it triggers dysfunctional cellular signaling. This can lead to the development of tumors, cell invasion, and metastasis. Abnormal met signaling is particularly invasive and metastatic and is implicated in cancers of the prostate, brain, kidney and liver, which often carry a poor prognosis.
Deactivating Abnormal Met Activity
Geldanamycin inhibits met/HGF-mediated cancer cell invasion by deactivating met’s molecular chaperone, heat shock protein 90 (Hsp90). Heat shock proteins (Hsps) are naturally produced by cells in response to heat or stressful conditions in order to protect the cell from damage. In non-stressful conditions, hsps act as molecular chaperones, or agents that stabilize and guide other proteins through their formation, folding and transport.
Geldanamycin bound to the ATP-pocket of Hsp90. Image courtesy of the European Bioinformatics Institute.
Hsp90 is an ATP-binding protein, which is particularly important for the cellular function of proliferation. In an abnormal process, Hsp90 is the first link in the chain that leads to the proliferation of invasive cells. However, Hsp90 is uniquely affected by geldanamycin. Geldanamycin deactivates Hsp90 by preventing it from binding to ATP. This deactivates Hsp90 and results in the degradation of its client proteins, including met, during their formation, which inhibits abnormal signaling and the spread of malignant cells.
Research to Date
Lab Results
Despite geldanamycin’s powerful anti-tumor qualities, laboratory tests repeatedly indicate that the side effects, specifically hepatotoxicity (liver toxicity), limit its uses as a cancer drug and render it a poor candidate for clinical trials. This discovery, however, led to the development of geldanamycin analogues (particularly 17-AAG), which have equivalent anti-tumor properties, but reduced toxicity.
Current Research
Results from the Van Andel Research Institute (VAI) clinical trials of 17-AAG published in the March 2011 edition of the Proceedings of the National Academy of the Sciences detail a potential explanation for geldanamycin’s side effects, which may help to improve drug synthesis with an even greater reduction in toxicity for future clinical trials. In a press release issued by VAI, George Vande Woude, head of the research study, stated, ‘if there is a chance of decreasing the toxicity of geldanamycin and 17-AAG, it would be a boon in the treatment of cancer.’ Further research into these results is necessary for clarifying the drug’s mechanism of action and establishing new protocol for geldanamycin, 17-AAG drug development.
References
Xie, Q., et al. Benzoquinone Ansamycin 17AAG Binds to Mitochondrial Voltage-dependent Anion Channel and Inhibits Cell Invasion. (2011). Accessed November 20, 2011.
Van Andel Research Institute News. Van Andel Research Institute Finding Could Lead to Reduced Side Effects in Anti-Cancer Antibiotics. (2011). Accessed November 20, 2011.
Panaretou, B., et al. ‘ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo’. (1998). EMBO Journal, 17, 4829-4836.
Webb, C., et al. ‘The geldanamycins are potent inhibitors of the HGF/SF-Met-Urokinase Plasminogen Activator-Plasmin Protelolytic Network’. (2000). Cancer Research, 60(2), 342-349.
