Quercetin and Oncogenic RAS: No Gas, No Growth!

I have just linked a couple of news items €”on quercetin and oncogenic RAS €”whose consequences may be significant to us MMers. Before I go on, though, what is this RAS business? Simply put, RAS is a gene that can mutate and become overactive, leading to the development of cancer. In this dangerously altered state, it is known as oncogenic RAS, and is present in almost one-third of all cancers, according to a recently published Duke Medical news release, see http://tinyurl.com/34x3oo. According to these Duke researchers, attempts at inhibiting this mutated form of the RAS gene have failed so far. Therefore, they looked at inhibiting the cytokine activated by oncogenic RAS, and guess what? That cytokine just happens to be Interleukin-6 (yes, our infamous pro-inflammatory IL-6!). The Duke University researchers also found that angiogenesis was reduced by inhibiting the production of IL-6, and that “‘IL-6 was like the gas pedal driving the growth of tumors,’ Counter said. ‘No gas, no growth, which is exactly what we saw when we inhibited IL-6 in tumors.’ Counter is encouraged that even though these findings are in cell culture and animal models, therapies based on targeting IL-6 in cancers driven by the ras oncogene could be tested in humans in the near future. [ ] A phase II trial is underway testing a monoclonal antibody against IL-6 for patients with multiple myeloma, a cancer that depends on IL-6 but is not known to have a connection to the ras oncogene. If the results of this trial are positive, studies might begin in ras-dependent cancers. Counter’s group is actively pursuing the idea that such an antibody may inhibit pancreatic cancer growth in mouse models. If these results are positive, this will open the door for Duke oncologists to organize a clinical trial to test the agent in human cancer patients.” The abstract of the Duke study can be read here: http://tinyurl.com/23merm

The question then arises: is oncogenic RAS present in MM? As you may have guessed from the above-mentioned Duke Medical news release, the answer is: yes, it is, in a certain percentage of patients which seems to vary from study to study. Not surprising, I would add, since we are all so different. A 1992 study (http://tinyurl.com/ytb863) showed that RAS gene mutations were present in 47% of the MM patients (14 out of 30 patients). I thought the following finding was significant: RAS gene mutations were more frequently observed in patients with fulminating disease (10/15, 67%) than in patients with less aggressive forms of the disease (4/15, 26%). So, oncogenic RAS seems to be connected to a more aggressive form of MM. This would appear to be confirmed by the results of a 1989 study (http://tinyurl.com/yux83g): While the mechanism of occurrence and biological role of ras activation in MM remains to be elucidated, the preliminary correlations observed in this study between the presence of ras oncogenes and poor therapeutic response suggest that further investigations of the possible prognostic significance of these alterations are necessary. According to a more recent Italian study, published in March 2007 (http://tinyurl.com/2bfugg) Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). These mutations were detected in 20% of 81 newly diagnosed MM patients. The abstract concludes, however, that these mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities.

Another study, published in Blood in 2003 (full study: http://tinyurl.com/23e48r), looks at pathways activated by oncogenic ras that may stimulate IL-6-independent growth, and concludes: In summary, we have identified several signal pathways in myeloma cells constitutively activated by expression of mutated ras genes. Our results also suggest that these pathways provide excellent molecular targets for future therapy.

Why am I writing about this today? Because I just finished reading a study titled Quercetin mediates preferential degradation of oncogenic Ras and causes autophagy in Ha-RAS-transformed human colon cells and published in Carcinogenesis in May 2007 (abstract: http://tinyurl.com/22byoz; full text: http://tinyurl.com/23clc8) showing that quercetin downregulates the levels of oncogenic RAS in cancer cells. How about that? The study suggests that quercetin be used in cancers with frequent mutations of RAS genes. Interestingly enough, quercetin inhibits oncogenic RAS but not normal RAS. Excellent. Sure, this study is about colon cancer cells, but I think the implications could apply to MM as well, given the IL-6 connection. Therefore, I believe we MMers have another GOOD reason to keep taking quercetin (or to start taking it!). Indeed, I couldn’t have received a better birthday present (except the news that J.C. Rowling has decided to continue writing more chapters in the Harry Potter series! 😉 )

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