Abstract
Phosphatidylserine (PS) is normally located in the inner leaflet of the membrane bilayer of healthy cells, however it is expressed at high levels on the surface of cancer cells. This has allowed for the development of selective therapeutic agents against cancer cells (without affecting healthy cells). SapC-DOPS is a PS-targeting nanovesicle which effectively targets and kills several cancer types including pancreatic, lung, brain, and pediatric tumors. Our studies have demonstrated that SapC-DOPS selectively induces apoptotic cell death in malignant and metastatic cells, whereas untransformed cells remain unaffected due to low surface PS expression. Furthermore, SapC-DOPS can be used in combination with standard therapies such as irradiation and chemotherapeutic drugs to significantly enhance the antitumor efficacy of these treatments. While the PS-targeting nanovesicles are a promising selective therapeutic option for the treatment of cancers, more preclinical studies are needed to fully understand the mechanisms leading to non-apoptotic PS expression on the surface of viable cancer cells and to determine the effectiveness of SapC-DOPS in advanced metastatic disease. In addition, the completion of clinical studies will determine therapeutic effects and drug safety in patients. A phase I clinical trial using SapC-DOPS has been completed on patients with solid tumors and has demonstrated compelling patient outcomes with a strong safety profile. Results from this study are informing future studies with SapC-DOPS.935RmdkxjZcSE6EkqR1Q7e videoGraphical abstract
Highlights
Phosphatidylserine (PS) is an anionic phospholipid, important for the functioning and integrity of the eukaryotic cellular membrane [1]
When saposin C or DOPS were used individually to treat pancreatic cancer cells, apoptosis was not induced. These results suggest that both Saposin C and DOPS are required for optimal cytotoxic effects of SapC-DOPS [15]
Our studies have demonstrated that SapC-DOPS selectively induces apoptotic cell death in malignant pancreatic cells, whereas untransformed pancreatic ductal epithelial cells remain unaffected [13–15, 38]
Summary
Phosphatidylserine (PS) is an anionic phospholipid, important for the functioning and integrity of the eukaryotic cellular membrane [1]. (2020) 18:6 include its consistent selective targeting and killing of cancer cells while being tolerated in healthy cells – this phenomenon has been reflected in results of phase I clinical trials where SapC-DOPS showed a strong safety profile [24, 25]. SapC-DOPS [1] utilizes multiple mechanisms to induce cancer cell death including caspase 9 cleavage and lysosomal membrane permeability [2] is capable of crossing the blood-brain tumor barrier and [3] enhances the effects of existing therapies [9, 10, 23, 26].
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