Can Fish Oil Interfere with Chemotherapy?

Abstract & Commentary

By Randy Horwitz, MD, PhD, Medical Director, Arizona Center for Integrative Medicine; Assistant Professor of Medicine, University of Arizona College of Medicine, Tucson. Dr. Horwitz reports no financial relationships relevant to this field of study.

Synopsis: This basic science paper explores the role of the tumor microenvironment in the development of tumor resistance to chemotherapy. Two distinct fatty acid molecules, endogenously produced by cancer cells in response to platinum-based chemotherapy drugs, were found to confer significant tumor chemoresistance. Remarkably, these two fatty acids also were shown to be present in several commercial fish oil products, and, of potential import to clinicians, the oral administration of small amounts of these fish oils induced tumor resistance to cisplatin in a mouse tumor model.

Source: Roodhart JM, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011;20:370-383.

Tumor resistance to chemotherapeutic agents presents a major obstacle in the successful treatment of cancer. Two types of chemoresistance have been described: an intrinsic, tumor cell-initiated event that develops slowly, and a more rapid, reversible resistance thought to be mediated by the tumor's surrounding stromal cells and associated molecules — the tumor's "microenvironment." This latter effect has remained an enigma until recently.

Evidence presented in this paper points toward the mesenchymal stem cell (MSC) as the cell that is directly responsible for the tumor's microenvironment. The MSC is pluripotent, and as such is capable of becoming an adipocyte, osteoblast, chondrocyte, or fibroblast under certain stimuli. MSCs are recruited in large numbers to the stroma of developing tumors, where they can stimulate tumor growth, angiogenesis, and metastatic spread. Their power to impart tumor resistance is significant, since as few as 50,000 of these cells, when administered intravenously, are sufficient to abolish the antitumor effects of cisplatin in two different murine tumor models. Their influence appears to be mediated by something other than local cellular interactions: if the MSCs are injected subcutaneously at a site distant from the tumors, as few as 1000 MSCs were sufficient to induce partial resistance to cisplatin, suggesting that there is a soluble or hormonal factor produced by the stimulated MSCs that is responsible for the action (i.e., cell-to-cell contact was not needed). This was reinforced by the observation that the injection of "conditioned media" (cell-free media made from MSCs co-cultured with a platin drug) inhibited the tumoricidal activity of cisplatin in tumor-bearing mice.

In addition, the researchers showed that the resistance conferred by MSCs can be extrapolated to other platinum-based drugs, including oxaliplatin and carboplatin, but not to other non-platinum based chemotherapeutic drugs (5-FU or irinotecan).

So what is this magic "chemo-resistance factor" secreted by the MSCs? It appears to be a fatty acid named KHT (12-oxo-5,8,10-heptadecatrienoic acid), as well as its precursor, KKT (hexadeca-4,7,10,13-tetraenoic acid). As little as 2 pM of either one of these injected into tumor-bearing mice will rapidly induce complete resistance to platin chemotherapy. Further, when MSCs are incubated with platin-containing compounds, their endogenous production of KHT and KKT goes up 3-fold. The authors call these 2 fatty acids "platinum-induced polyunsaturated fatty acids" (PIFAs).

They report some fascinating human correlates: Elevated levels of MSCs are seen in humans with metastatic tumors relative to lone tumors. In addition, it appears that platin-stimulated MSCs obtained from humans can induce resistance to chemo when used in the mouse model.

Now, on to the alternative medicine-relevant focus. It turns out that the PIFAs are abundantly represented in commercial fish oil products and algae extracts. They don't specifically name which ones were used in the experiments, but an oral dose of 100 ul (10-6 liters, or about 2 drops) of commercial fish oil (or algae extract) fed to tumor-bearing mice was sufficient to inhibit the activity of cisplatin significantly. In fact, fish oil neutralized the effect of the chemotherapeutic drug in two different murine tumor models. However, when the researchers used a purified EPA preparation (as opposed to "whole" fish oil), the EPA alone did not affect the antitumor effects of cisplatin. In fact, the purified EPA seems to actually make the cisplatin more tumoricidal (but not significantly so).

The researchers state that both commercial fish oil and the algae-derived product induced a "complete resistance to chemo at doses similar to the advised daily dose in humans."

Commentary

This is a complex basic science paper with clinical implications, especially for those of us involved in the care of patients with cancer. There are clearly differences between the experimental mouse tumor models used in this study and human cancers, but the data presented in this study are provocative and deserve attention.

A plethora of research has explored omega-3 (specifically fish oil) intake and the incidence of malignancy in humans. Many studies showed no association. One exception, the EPIC (European Prospective Investigation into Cancer and Nutrition) study, followed more than 475,000 Europeans for an average of 5 years, and attempted to correlate meat or fish intake with malignancy. Fish intake was inversely associated with colorectal cancer. Those consuming 3 ounces of fish daily reduced their risk of colon cancer by nearly a third, relative to those averaging less than 0.5 ounces of fish daily.1 (In case you are wondering, red meat was positively associated with colon cancer.)

Few studies, however, have examined the interaction of fish or fish oils in patients undergoing active chemotherapy, especially with platinum-based agents. One animal study did investigate the effect of omega-3 fats and cisplatin on the level of pulmonary tumor load in a mouse model of lung carcinoma.2 Mice were injected with a murine lung cancer cell line in the foot pad, and several days later, the lungs were assessed for metastatic tumor load.

Mice were given diets containing either fish oil or soybean oil (isocaloric). Those mice fed the fish oil diet exhibited significantly less tumor spread to the lungs relative to those fed a soybean oil diet, suggesting a protective effect of the fish oil.

When the soybean oil-fed mice were treated with cisplatin, the metastatic tumor load was unaffected; the cisplatin had virtually no effect. This was interesting, as the tumor previously had been shown to be cisplatin-sensitive. When the fish oil-fed mice were treated with cisplatin, the metastatic spread decreased moderately relative to soybean-fed animals (no statistical significance was reported).

However, when we compare metastatic tumor spread in the fish oil-fed mice with the cisplatin-treated fish oil-fed mice, we see a marked attenuation of this anticancer effect of the cisplatin. That is, the results with the fish oil diet alone were significantly better than with the fish oil diet plus cisplatin. This suggests that fish oil alone inhibits metastatic spread somewhat, while the addition of cisplatin to fish oil attenuates this desired result. Perhaps this observation represents a similar phenomenon to that seen in the Roodhart paper. Taken as a whole, these papers certainly give pause to the potential interactions between fatty acid ingestion and tumor growth/chemotherapy responsiveness.

So what lessons can we glean? Many naturally derived substances prescribed in integrative medicine are used with impunity, owing to the benign nature of the source. Fish oil is a good example; a daily supplement dose often is equated with a large serving of a fatty fish (i.e., salmon), and thus is regarded as very safe. However, there are several challenges in making sweeping recommendations for fish oil use in patients with cancer: First, many oncologists are choosing therapeutic protocols based upon results from clinical studies conducted in populations that are typically not using regular doses of fish oil — most individuals do not eat daily servings of fish as a matter of course. In addition, there are few controlled studies looking at the potential interactions between foods or food components and biochemical therapeutics. In fact, I suspect that even among prescient observers, few would have predicted this profound effect of fish oil in a tumor model.

Until we have more details and corroborating studies, I would not recommend fish oil as an adjunctive therapy to patients receiving platinum-based chemotherapy. If a patient is considering fish oil supplementation during platin-based chemotherapy, it would be important to contact the manufacturers of commercial fish oil products to inquire about the KHT and KKT content of the oil. As described in the paper, very little PIFA is required to negate the chemotherapeutic effect of the platinum-based therapy in vivo.

References

1. Norat T, et al. Meat, fish, and colorectal cancer risk: The European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst 2005;97:906-916.

2. Yam D, et al. Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin. Cancer Chemother Pharmacol 2001;47:34-40.