Gossypol analogue

Remember my post on gossypin? Okay, well, today’s post has nothing at all to do with gossypin. (Hehe, sorry, couldn’t resist. ) But really, the word "gossypin" sounds like the substance I am about to discuss: "gossypol," which I thought was a derivative of gossypin, at first. But no, gossypin is a flavone extracted from the tropical rose mallow plant, whereas today’s protagonist, gossypol, is a polyphenol derived from the cotton plant. So, different compounds.
Gossypol, I read online, has been used for centuries against malaria and as a male contraceptive in China. The cotton plant produces gossypol to protect itself from the damage caused by pesky insects. It’s a toxin that inhibits the reproduction of insects and also of humans (mammals in general). Anyway, what I found interesting is that gossypol is now being studied for its anticancer properties. An all-too-familiar story!
The new edition of “Blood” (March 15 2008) has a study on a gossypol semi-synthetic analogue called "apogossypol" that apparently is more effective than gossypol against Bcl-2, an anti-apoptotic gene that almost certainly has a lot to do with the chemoresistance of myeloma cells. Brief aside: you can do a search here for Bcl-2, just scroll to the bottom of my Blogroll until you reach a "search" box; see in particular my August 27 2007 post titled “Survivin MM with curcumin.”
Sherlock (grazie!) sent me the full study; you can view the abstract here: http://tinyurl.com/ytsvdh The study begins with a look at the above-mentioned Bcl-2, which is overexpressed in many cancers and leukaemias and protects tumours and leukemic cells from kicking the bucket when exposed to chemotherapy, hormonal treatment or radiation. Bcl-2 has thus become a target for cancer treatment, especially where B-cell malignancies are concerned (non-Hodgkin lymphoma and CLL, in particular).
The study tells us that another gossypol analogue, AT-101, is being tested right now in Phase 1 and 2 clinical trials on patients with solid tumours, lymphomas and leukaemia. I checked to see what kind of clinical trials were testing gossypol, and there are twelve trials for different kinds of cancer ranging from brain to prostate cancer. And, of course, B-malignancies. The main problem of AT-101, though, appears to be the GI toxicity caused by its bothersome aldehydes; we don’t need to know what these are exactly, just that their removal eliminates any GI problems. The "Blood" study researchers did just that: they removed the aldehydes, thus creating apogossypol, which shows “superior blood concentrations over time […] compared with gossypol, due to slower clearance of the compound.”
Toxicity: the researchers tested the toxicity of gossypol and its analogue on normal female Balb/c mice (okay, I confess that I still shudder with horror when I think of all the suffering lab animals around the world…and to tell the truth, if someone told me, “it’s either you or that mouse,” it would be a tough choice for me to make, as silly as that probably sounds. If the choice were between me or a cat, well, you can imagine what my answer would be…now why can’t experiments be done on those maddening tiger mosquitoes??? ).
Back to the study. Well, apogossypol turned out to be less toxic than its parent compound. If you want to read more details, I will be happy to forward the study to you. Other results: unlike apogossypol, gossypol was toxic to the liver, caused GI problems and made the mice lose weight. Neither substance caused any kidney toxicity or heart trouble. Ok, I’ve read enough about the poor dear lab mice. Basta!
In vitro findings (phew, much better: I don’t have as much sympathy for cancer cells…). The researchers used “cultured B-cell lymphoma and CLL leukemia cells.” In both cell cultures, apogossypol was more lethal than gossypol.
The gist of the study: “The preclinical data presented here show superior efficacy and markedly reduced toxicity of apogossypol compared with gossypol, and thus indicate that further development of apogossypol for B-cell malignancies is warranted.” Well, interesting study. Another piece of the puzzle, perhaps. Only time will tell…

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