Year-end Sale % OFF 
Abstract
Oncolytic peptides and peptidomimetics are being optimized for the treatment of cancer by selecting agents with high cytotoxic potential to kill a maximum of tumor cells as well as the capacity to trigger anticancer immune responses and hence to achieve long-term effects beyond therapeutic discontinuation. Here, we report on the characterization of two novel oncolytic peptides, DTT-205 and DTT-304 that both selectively enrich in the lysosomal compartment of cancer cells yet differ to some extent in their cytotoxic mode of action. While DTT-304 can trigger the aggregation of RIP3 in ripoptosomes, coupled to the phosphorylation of MLKL by RIP3, DTT-205 fails to activate RIP3. Accordingly, knockout of either RIP3 or MLKL caused partial resistance against cell killing by DTT-304 but not DTT-205. In contrast, both agents shared common features in other aspects of pro-death signaling in the sense that their cytotoxic effects were strongly inhibited by both serum and antioxidants, partially reduced by lysosomal inhibition with bafilomycin A1 or double knockout of Bax and Bak, yet totally refractory to caspase inhibition. Both DTT-304 and DTT-205 caused the exposure of calreticulin at the cell surface, as well as the release of HMGB1 from the cells. Mice bearing established subcutaneous cancers could be cured by local injection of DTT-205 or DTT-304, and this effect depended on T lymphocytes, as it led to the establishment of a long-term memory response against tumor-associated antigens. Thus, mice that had been cured from cancer by the administration of DTT compounds were refractory against rechallenge with the same cancer type several months after the disappearance of the primary lesion. In summary, DTT-205 and DTT-304 both have the capacity to induce immunotherapeutic oncolysis.
Highlights
Peptides can be synthetically generated and potentially provide pharmacological leads or final agents for multiple purposes
In cells in which the plasma membrane was still intact and retaining the cytoplasm, lipid droplets in the cytoplasm were a prominent morphological feature (Fig. 1a) that was induced in a dose-dependent fashion (Fig. 1b, c), as determined by transmission electron microscopy
Staining with the red fluorescent lipophilic dye Nile red confirmed the formation of lipid droplets in the cytoplasm of cells treated with DTT-205 or DTT-304 that occurred in a time and dose-dependent fashion (Fig. 1d–f)
Summary
Peptides can be synthetically generated and potentially provide pharmacological leads or final agents for multiple purposes. Oncolytic, LTX-401, an amphipathic β(2,2)-amino acid derivative, tends to enrich in the Golgi apparatus and dismantles the organelle before mitochondrial integrity is compromised[4,8,13]. This mitochondrial step of the cell death cascade appeared to be important for cell death induction by both LTX-315 and LTX-401, because knockout of the proapoptotic multidomain BCL2 family proteins BAX and BAK attenuated cell killing by both LTX-315 and LTX-4018,11. These differences and similarities illustrate the complexity of pro-death signaling mediated by agents that apparently share comparable physicochemical properties
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
