Targeting phosphatidylserine for Cancer therapy: prospects and challenges

Abstract

Cancer is a leading cause of mortality and morbidity worldwide. Despite major improvements in current therapeutic methods, ideal therapeutic strategies for improved tumor elimination are still lacking. Recently, immunotherapy has attracted much attention, and many immune-active agents have been approved for clinical use alone or in combination with other cancer drugs. However, some patients have a poor response to these agents. New agents and strategies are needed to overcome such deficiencies. Phosphatidylserine (PS) is an essential component of bilayer cell membranes and is normally present in the inner leaflet. In the physiological state, PS exposure on the external leaflet not only acts as an engulfment signal for phagocytosis in apoptotic cells but also participates in blood coagulation, myoblast fusion and immune regulation in nonapoptotic cells. In the tumor microenvironment, PS exposure is significantly increased on the surface of tumor cells or tumor cell-derived microvesicles, which have innate immunosuppressive properties and facilitate tumor growth and metastasis. To date, agents targeting PS have been developed, some of which are under investigation in clinical trials as combination drugs for various cancers. However, controversial results are emerging in laboratory research as well as in clinical trials, and the efficiency of PS-targeting agents remains uncertain. In this review, we summarize recent progress in our understanding of the physiological and pathological roles of PS, with a focus on immune suppressive features. In addition, we discuss current drug developments that are based on PS-targeting strategies in both experimental and clinical studies. We hope to provide a future research direction for the development of new agents for cancer therapy.

ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine

“…In this regard, it was recently shown that a chemical activator of p53 in combination with an antibody that targets PS on tumor blood vessels and disrupts tumor vasculature effectively inhibits metastasis of p53-expressing TNBC cells to the lungs in a mouse model (44). Our study further illustrated that PS should serve as a target for cancer therapy, as it is an essential component of the cancer cell membrane and plays an important role in maintaining cancer cell viability and metastasis (45)(46)(47).…”

Group and Basis Restricted Non-Negative Matrix Factorization and Random Forest for Molecular Histotype Classification and Raman Biomarker Monitoring in Breast Cancer

“…[12][13][14][15][16]23 The insights on how glycogen and lipids (cholesterol, phosphatidylserine, and stearic acid) can be linked to PR/ER and Ki67 molecular histotypes and how this relates to RT are reported by RS for the first time to our knowledge, although these metabolites have been studied intensively in the cancer research community. [56][57][58][59][63][64][65][66][67][68] The motivation to add extra chemicals such as leucine and valine into the reference chemical library was to potentially investigate whether RS and the GBR-NMF-RF framework could track changes in protein or amino acids in the breast cell lines. Proteins are difficult to trace because the amino acid composition of proteins can vary greatly.…”

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…The overall lipid composition of the cancer cell resembles that of normal cells, however, the asymmetric distribution of lipid classes between the inner and outer leaflets, normally found in eukaryotic cell membranes [745], is lost; they instead display a substantial concentration of phosphatidylserine in the outer leaflet. The selective disruption of lipid membranes rich in phosphatidylserine becomes a possible mode of action for cancer therapy: anticancer peptides [746,747] or drugs affecting the membranes of cancer cells [748].…”