April 2013

Circumventing cancer’s ability to cheat death

How gedunin may help win the fight

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Courtesy of Piled Higher and Deeper by Jorge Cham

 
Over the past decade, scientists have been working feverishly to uncover the therapeutic potential of a class of molecules called heat shock proteins, which may provide the key to designing better cancer drugs.
 
Imagine this. What if the cells in your body had a way to sense when there was some sort of stressful condition and upregulated specific molecules (rallied the troops, if you will) to prevent your perfectly healthy cells from dying? Well, it does. Heat shock proteins sense the clear and present danger and report to duty. The proteins are, in fact, induced by heat and cellular stresses such as introduction of a toxic chemical in a process referred to as the heat shock response.
 
Sweet, right?! Yes — but not in the case of cancer. This elusive and often mysterious disease has an uncanny ability to hijack your body’s built-in protection mechanism for its own purposes. Instead of protecting healthy cells, heat shock proteins are often misused by cancer cells to protect themselves, allowing them to grow and divide, a process known as proliferation.
 
Scientists have tried to address this proverbial Catch-22 by designing compounds that inhibit heat shock proteins, namely Hsp90. These inhibitors bind the active N-terminal ATP-binding pocket in the protein, thereby making it inactive. The thought is that if you block Hsp90, you can prevent cancer cell proliferation and ultimately tumor growth.
 
If only it were that simple. What seemed like a viable approach in principle, proved to present a challenge in clinical trials. Unfortunately, it was found that the introduction of Hsp90 inhibitors themselves induce the heat shock response. The inhibitors upregulate the expression of yet another set of heat shock proteins — Hsp70 and Hsp27. These anti-apoptotic proteins prevent cell death, rendering the therapy designed to avoid cancer cell growth ineffective.
 
While one should appreciate the extensive efforts that the body makes to ensure the survival of our precious healthy cells, it brings into question: How can you circumvent the body’s built-in, pro-survival mechanisms (in this case the heat shock response) to effectively treat cancer using Hsp90 inhibitors?
 
“There are different classes of Hsp90 inhibitors. The main one that is in clinical trials is the one that inhibits the N-terminal ATP binding site of Hsp90. Targeting other parts of Hsp90, such as the ATP-binding sites in the C-terminus, interestingly does not induce the heat shock response. The other alternative … is to target co-chaperones of Hsp90. The co-chaperones are proteins that help Hsp90 to accomplish its role. These proteins are being heavily investigated,” says Ahmed Chadli, assistant professor in the Cancer Research Center at Georgia Regents University.
 
It turns out that researchers may need to look no further than nature for a solution. Recent reports have shown that gedunin, a natural compound isolated from the Meliacae family of plants, exhibits antiproliferative activity against tumor cells in several forms of cancer (1–3).
 
In the recent Journal of Biological Chemistry paper “Gedunin inactivates the co-chaperone p23 causing cancer cell death by apoptosis,” Chadli and collaborators sought to identify the molecular target of gedunin. Gedunin is a particularly attractive alternative to traditional Hsp90 inhibitors because the compound inhibits the Hsp90 machine without inducing the expression of Hsp27 and expresses very little of Hsp70.
 
Using a series of biochemical techniques, the team determined that gedunin selectively destabilizes steroid hormone receptors but not signaling kinase clients of Hsp90. According to Chadli, the ability of the compound to target one subset of Hsp90 clients is an advantage. “This may be a really great opportunity to address the cancers that are hormone-dependent like breast, ovarian and endometrial cancers. The idea is that if we can inactivate these steroid receptors without affecting the kinases that are also dependent on Hsp90, we may have (fewer) side effects.”
 
It also was shown that gedunin specifically binds to p23, a co-chaperone required for the stability of steroid receptors, and its binding site was mapped using molecular docking experiments. Functional assays ultimately determined that gedunin inhibits the molecular chaperoning activity of p23 and prevents its interaction with Hsp90. The interaction of gedunin and p23 was not only cytotoxic to cancer cells, but it also triggered caspase-7-mediated cleavage and inactivation of p23, resulting in cancer cell death by apoptosis.

logo for JBC News PodcastsClick here to listen to a JBC News Podcast interview with Ahmed Chadli about gedunin, Hsp90, p23 and the neem tree plant.

It appears that gedunin may be a viable option for avoiding the heat shock response upon Hsp90 inhibition. However, Chadli points out that more studies need to be done. “The next step is to do preclinical studies using gedunin on mice, and we will see if this compound in combination with prototypical Hsp90 inhibitors such as 17-allylamino-17-demethoxygeldanamycin will give a synergistic effect and better outcomes.” Looks like it’s time to bring in the reinforcements…

REFERENCES
  1. 1. Uddin, S.J. et al. Phytother. Res. 21, 757–761 (2007).
     
  2. 2. Kamath, S.G. et al. Int J. Gynecol. Cancer 19, 1564–1569 (2009).
     
  3. 3. Hieronymus, H. et al. Cancer Cell 10, 321–330 (2006).

Shannadora HollisShannadora Hollis (sholl002@umaryland.edu) received her B.S. in chemical engineering from North Carolina State University and is a Ph.D. student in the molecular medicine program at the University of Maryland, Baltimore. Her research focuses on the molecular mechanisms that control salt balance and blood pressure in health and disease. She is a native of Washington, D.C., and in her spare time enjoys cooking, thrift-store shopping and painting.

 

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