Potential of algal phosphatidylcholines containing ω3 fatty acids in the supportive therapy of leukemia and lymphoma
Phosphatidylcholine-bound ω3 fatty acids (ω3-PC) suppress homeostatic pathways with fundamental roles in tumorigenesis, metastasis, and tumor resistance. By attenuating pro-survival Akt activation, ω3-PC delays cell cycle progression and enhances apoptosis. ω3-PC also increases membrane rigidity, impairs cell migration, interferes with cytoskeleton dynamics, and serves as substrate for the biosynthesis of tumor-suppressive lipid mediators. Supported by the Phospholipid Research Center Heidelberg, the potential of ω3-PC in overcoming Akt-dependent tumor resistance has been explored in a former project [Inhibition of Akt by polyunsaturated phosphatidylcholine – A novel approach for anti-cancer therapy] and it has been found that the cytotoxic activities of distinct cytoskeleton-targeting agents are potentiated through Akt-dependent and -independent mechanisms. Strong differences between ω3-PC and saturated PC have been observed, and leukemia cell lines were identified as being exceptionally sensitive to ω3-PC, which prompts for the evaluation of the phospholipid in anti-leukemic therapy.1)2)3)4)
The next steps are to find a renewable and cheap source of ω3-PC, develop a bioactive formulation, and initiate pre-clinical studies on murine leukemia. By screening 23 macro- and microalgae, we recently identified a cost-efficient source of ω3-PC and will now establish a standardized procedure to obtain ω3-PC-rich fractions. In cooperation with other researchers, ω3-PC-rich liposomes will be prepared and characterized regarding their size, lamellarity, morphology, and stability. Bioactive liposomes for intravenous injection will be identified by in vitro screening using human HL-60 leukemia cells and then studied in combination with an anti-cytoskeleton agent in a human leukemia/lymphoma xenograft model. The effects of a synergistic co-administration of liposomes and the chemotherapeutic agent will be also evaluated. The biodistribution of ω3-PC in mouse and tumor tissues will be analyzed by lipidomic profiling. Focus will be placed on mitogenic kinases (including Akt), actin dynamics, anti-tumoral lipid mediators, (oxidative) stress signaling, and programmed cell death pathways including ferroptotic cell death. Follow-up studies on clinically relevant lymphoma and leukemia models and tumors of different origin will be designed according to the outcome of our pilot study.
In conclusion, the project will explore the (pre)-clinical potential of ω3-polyunsaturated phospholipids in supportive anti-leukemic therapy and provide fundamental insights into their physiologically relevant molecular mechanisms.
Benefit for the community
More than 20,000 people develop blood cancer in Germany each year, and the number is increasing because of an aging society. The 5-year survival rates of leukemia, lymphoma or myeloma are still below 50 to 90% despite novel therapies that decreased death rates during recent years. Hence, there is an urgent need for further therapeutic advances. Based on comprehensive mechanistic studies in vitro, ω3-PC were proposed as effective supplement to reduce tumor resistance, in particular for blood cancer cell lines and in combination with cytoskeleton-targeting drugs. We will take first steps to translate the promising basic research into a biomedical application by initiating pre-clinical studies.
Arachidonoyl-phosphatidylcholine oscillates during the cell cycle and counteracts proliferation by suppressing Akt membrane binding
Proc. Natl. Acad. Sci. USA 110, 2546-2551
Vitamin A regulates Akt signaling through the phospholipid fatty acid composition
FASEB J. 31, 4566-4577
Targeting de novo lipogenesis as a novel approach in anti-cancer therapy
Br. J. Cancer 118, 43-51
Acetyl-CoA carboxylase 1 regulates endothelial cell migration by shifting the phospholipid composition
J. Lipid Res. 59, 298-311