Study summary · research use only
The penetratin sequence in the anticancer PNC-28 peptide causes tumor cell necrosis rather than apoptosis of human pancreatic cancer cells
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this human cell study, the authors examined the p53-derived peptides PNC-27 and PNC-28, from the human double minute 2 (hdm-2) binding domain attached to penetratin, in pancreatic cancer cells. MiaPaCa-2 cells were treated with PNC-28; necrosis was assessed via lactate dehydrogenase (LDH) release and apoptosis via proapoptotic proteins, with PNC-29 and a penetratin-free peptide (PNC-26) as controls. A plasmid encoding the p53 aa17-26 segment was transfected into MiaPaCa-2 and an untransformed rat pancreatic acinar cell line (BMRPA1). The abstract reports that PNC-28 treatment did not elevate proapoptotic proteins but elicited rapid LDH release, membrane pore formation, and dose-dependent killing, whereas transfected cells underwent apoptosis with elevated caspases-3 and 7 and annexin V. The authors conclude the penetratin sequence drives a shift toward necrosis initiated by membrane pore formation.
Abstract
PNC-27 and PNC-28 are p53-derived peptides from the human double minute (hdm-2) binding domain attached to penetratin. These peptides induce tumor cell necrosis of cancer cells, but not normal cells. The anticancer activity and mechanism of PNC-28 (p53 aa17-26-penetratin) was specifically studied against human pancreatic cancer. MiaPaCa-2 cells were treated with PNC-28. Necrosis was determined by measuring lactate dehydrogenase (LDH) and apoptosis as assayed for measuring elevation of proapoptotic proteins. PNC-29, an unrelated peptide, and hdm-2-binding domain p53 aa12-26 without penetratin (PNC-26) were used as controls. Since there is evidence that penetratin is required for tumor cell necrosis, we tested "naked" p53 peptide without penetratin by transfecting a plasmid that encodes p53 aa17-26 segment of PNC-28 into MiaPaCa-2 and an untransformed rat pancreatic acinar cell line, BMRPA1. Time-lapse electron microscopy was employed to further elucidate anticancer mechanism. Treatment with PNC-28 does not result in the elevation of proapoptotic proteins found in p53-induced apoptosis, but elicits rapid release of LDH, indicative of tumor cell necrosis. Accordingly, we observed membrane pore formation and dose-dependent killing. In direct contrast, transfected MiaPaCa-2 cells underwent apoptosis, and not necrosis, as evidenced by expression of high levels of caspases-3 and 7 and annexin V with background levels of LDH. These results suggest that PNC-28 may be effective in treating human pancreatic cancer. The penetratin sequence appears to be responsible for the fundamental change in the mechanism of action, inducing rapid necrosis initiated by membrane pore formation. Cancer cell death by apoptosis was observed in the absence of penetratin.
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