The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients.
Chemotherapy remains the primary treatment for most disseminated cancers. However, response to chemotherapy is often transient, and the development of resistance is one of the most significant obstacles to effective cancer therapy. We now show that mesenchymal stem cells (MSCs) activated by platinum-based chemotherapy secrete two unique fatty acids that, in minute quantities, confer resistance to multiple types of chemotherapy. This highlights an undesired role for stem cells in cancer treatment and reveals a potent effect of two relatively unknown fatty acids. Finally, our results reveal a therapeutic approach to enhance the clinical benefit of chemotherapy by blocking the release of these fatty acids from MSCs via inhibition of cyclooxygenase-1 or thromboxane synthase.
Reports that Fish Oil Reduces Chemotherapy Effectiveness are Premature
Roodhart JM Daenen LG Stigter EC Prins HJ Gerrits J Houthuijzen JM Gerritsen MG Schipper HS Backer MJ van Amersfoort M Vermaat JS Moerer P Ishihara K Kalkhoven E Beijnen JH Derksen PW Medema RH Martens AC Brenkman AB and Voest EE (2011). Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 20:370-383.
While the preclinical experiments reported in the present publication were well designed and executed, the potential applicability of the results to clinical chemotherapy is dependent upon the outcome of additional research. The Results can and should be used to design additional studies either to further the development of new chemotherapeutic agents and/or to identify strategies to enhance current chemotherapy effectiveness by decreasing drug resistance.
What’s the Controversy?
The PIFA, 16:4(n-3), is present in commercially available fish oil products and individuals with cancer, like the rest of the population, are frequent users of such products. The investigators fed tumor-bearing mice either purified PIFAs or commercially available fish oil products and treated them with the chemotherapeutic agent cisplatin. PIFAs induced resistance to cisplatin. In addition, at doses similar to those taken by humans, commercially available fish oil products resulted in neutralization of the antitumor effects of cisplatin. According to the authors, the results provide support for the clinical relevance of this fatty acid in the development of resistance to chemotherapy.
What Else Should You Know?
During this calendar year alone, there have been three publications reporting on research about the long-chain omega-3 fatty acids increasing chemotherapy efficacy. While the results are exciting, they, like the results from the controversial publication, are just pieces of the puzzle, not a basis for making any recommendations. For the positive body of evidence, further research is warranted to identify specific mechanisms by which long-chain O-3s increase chemotherapy efficacy and to determine the optimal cellular/membrane levels of long-chain O-3s required to promote these mechanisms, such that these fatty acids may be prescribed as adjuvants to chemotherapy.
Results from Das and Madhavi (2011) suggest that long-chain omega-3 fatty acids have tumoricidal action and are capable of enhancing the cytotoxic action of anti-cancer drugs, specifically on drug-resistant cells by enhancing drug uptake and reducing its efflux.
Results from Kuan et al. (2011) suggest that long-chain omega-3 fatty acids promote the cytotoxicity of the chemotherapeutic agent Paclitaxel in the human colon cancer Caco-2 cell line.
Results from Molinari et al. (2011) suggest that DHA induces calreticulin exposure and thus represents a potential novel anticancerimmunogenic chemotherapeutic agent.
Global Organization for EPA and DHA Omega-3s (2011). Reports that Fish Oil Reduces Chemotherapy Effectiveness are Premature [Peer commentary on the paper “Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids” by Roodhart JM Daenen LG Stigter EC Prins HJ Gerrits J Houthuijzen JM Gerritsen MG Schipper HS Backer MJ van Amersfoort M Vermaat JS Moerer P Ishihara K Kalkhoven E Beijnen JH Derksen PW Medema RH Martens AC Brenkman AB and Voest EE (2011). Cancer Cell 20:370-383].
Das UN and Madhavi N (published ahead of print Sept 14, 2011). Effect of polyunsaturated fatty acids on drug-sensitive and resistant tumor cells in vitro. Lipids Health Dis doi:10.1186/1476-511X-10-159.
Kuan CY Walker TH Luo PG and Chen CF (2011). Long-chain polyunsaturated fatty acids promote paclitaxel cytotoxicity via inhibition of the MDR1 gene in the human colon cancer Caco-2 cell line. J Am Coll Nutr 30:265-273.
Molinari R D'Eliseo D Manzi L Zolla L Velotti F and Merendino N (2011). The n3-polyunsaturated fatty acid docosahexaenoic acid induces immunogenic cell death in human cancer cell lines via pre-apoptotic calreticulin exposure. Cancer Immunol Immunother 60:1503-1507.