Dr. Weeks’ Comment: Healthy cells resist the oxidation and damage from chemotherapy. Fish oil replenishes our stores of essential fatty acids and so it is a no-brainer (but of ignored fact) that fish oil enhances health. But which cells are being rendered resistant to the ravages of chemotherapy: the cancer cells (the target) or the other innocent, non-cancerous cells (not the target)? Well, in the presence of insulin (IPT) the cellular membrane structure and function are modified so as to be more permeable to chemotherapy (compared to healthy cells). So clinically speaking, we see that essential fatty acids reduce side-effects of chemotherapy. Read on!
Fatty Acids in Humans, Fish May Induce Chemo Resistance
September 20, 2011 ”” Acquired resistance to chemotherapy is a major barrier to optimal cancer treatment and is often thought to be the result of changes in cancer cells themselves. But now Dutch researchers have identified 2 fatty acids that the body excretes and appear to cause resistance to multiple types of chemotherapy, according to a paper published online September 12 in Cancer Cell.
In an experimental study, researchers from University Medical Center Utrecht, the Netherlands, observed that endogenous mesenchymal stem cells (MSCs) become activated by treatment with platinum-based chemotherapy and secrete unique fatty acids that protect tumor cells against a range of chemotherapeutic agents.
The fatty acids were identified as polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT), and hexadeca-4,7,10,13-tetraenoic acid [16:4(n-3)]. In minute amounts, these fatty acids were able to induce resistance.
“Where resistance to chemotherapy is concerned, we usually believe that changes in the cancer cells themselves have occurred,” said senior author Emile Voest, MD, medical oncologist at the center.
“Now we show that the body itself secretes protective substances into the blood that are powerful enough to block the effect of chemotherapy,” he said in a statement.
The 2 PIFAs associated with chemotherapy resistance are also found in commercially produced fish oil supplements containing omega-3 and omega-6 fatty acids, as well as in some algae extracts. Fish oil products are often used by patients with cancer because of their perceived positive health effects, write the authors. These effects include prevention of cachexia and cardiovascular events, inflammation, tumor growth, and reduction of adverse events associated with chemotherapy.
Avoid Fish Oil Supplements?
When these products were used in experiments conducted in mice, the tumors became insensitive to chemotherapy, explained study author Laura G.M. Daenen, MD, also from the University Medical Center Utrecht.
“The resistance is due to these two specific PIFAs,” Dr. Daenen told Medscape Medical News. “EPA and DHA [eicosapentaenoic acid and docosahexaenoic acid] were used as controls and, importantly, did not induce resistance in our mouse models.”
“Therefore, there is no need to avoid these fatty acids, or products containing these fatty acids, even in high doses,” she added.
Dr. Daenen noted that they have not tested any other food products for the presence of these PIFAs, so it is unknown whether they can be found in other foods. And the experiment was also conducted by using 2 commercially available fish oil products and homogenized extracts from Ulva Pertussa algae. These findings to not necessarily extrapolate to the consumption of fish, she pointed out.
“Concerning the consumption of fish, even if these PIFAs might be present, their concentrations will presumably be very, very low,” Dr. Daenen said. “We now have absolutely no reason to believe that fish consumption could have an effect on chemotherapy actions.
So should patients undergoing chemotherapy avoid fish oil supplements during their treatment?
“Our conclusions are based on mouse models,” said Dr. Daenen. “Since the data is indeed preliminary and based on mouse experiments, we feel that other practicing clinical oncologists should make their own choice about their advice to patients.”
But she pointed out that for patients at the University Medical Center Utrecht, the advice is as follows: “Whilst waiting for the results of further research, we currently recommend that these products should not be used whilst people are undergoing chemotherapy.”
This a first-rate study of the effect of conditioned media from stem cells incubated with cisplatin, commented Bruce Chabner, MD, who was approached by Medscape Medical News for independent commentary.
“The conditioned media contain a mixture of fatty acids, and these products are capable of inducing resistance to various chemotherapy agents,” said Dr. Chabner, a professor of medicine at Harvard Medical School and director of clinical research, Massachusetts General Hospital Cancer Center, Boston. “These studies are done in mice with relatively high doses of drug, and have uncertain but potential applicability to clinical chemotherapy.”
He emphasized that it “will be necessary to conduct experiments in people, using inhibitors of fatty acid synthesis, to determine whether it has relevance to human experience. It is potentially important.”
Microenvironment Plays Key Role
Although several tumor cell-intrinsic mechanisms of drug resistance have already been identified, it is becoming increasingly clear that the tumor microenvironment plays a key role in the development of drug resistance, say the authors.
Acquired tumor cell-intrinsic resistance generally develops over time, but environment-mediated drug resistance is rapidly induced by signaling events from the tumor microenvironment, they write. It is also likely to be reversible because removing the microenvironment will restore the drug sensitivity.
Tumors actively modulate their microenvironment by recruiting inflammatory cells and bone marrow-derived cells, which, in turn, are able to respond to therapy in an immediate “seek and repair” manner, most probably to support tissue regeneration, note the authors. A subgroup of these cells, the MSCs, have garnered recent attention as mediators of cancer progression.
In the current study, the researchers examined the role that MSCs might play in the development of resistance to chemotherapy.
In a mouse model, they noted that both intravenous and subcutaneous injections of MSCs induced resistance to cisplatin. Interestingly, in vivo resistance was induced by MSCs not only for cisplatin but for oxaliplatin (10 mg/kg) and carboplatin (100 mg/kg), but not with 5-fluoroucil (100 mg/kg) or irinotecan (100 mg/kg).
Further investigation revealed that MSC-induced resistance is mediated by the release of polyunsaturated fatty acids, and identified the 2 unique fatty acids that conferred the resistance. “This highlights an undesired role for stem cells in cancer treatment and reveals a potent effect of two relatively unknown fatty acids,” the authors write.
Validated in Human Cells
Finally, to validate the findings in patients with cancer, levels of MSCs were measured in the whole blood of 50 patients with different types of tumors. The authors found a significant increase in MSC counts in the peripheral blood of patients with metastatic disease compared with those who had undergone a radical resection of the tumor and had no residual disease.
These results indicated that MSCs are present in the circulation and will subsequently be exposed to chemotherapy. Also, the authors note that the number of circulating MSCs was similar to the number of MSCs sufficient to confer chemoresistance in mouse models.
The study was supported by grants from the Dutch Cancer Society and the Netherlands Metabolomics Centre. The authors have disclosed no relevant financial relationships.
Cancer Cell. Published online September 12, 2011. Abstract
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