Molecular Targeting of H/MDM-2 Oncoprotein in Human Colon Cancer Cells and Stem-like Colonic Epithelial-derived Progenitor Cells

Thadi, Anusha; Morano, William F.; Khalili, Marian; Babcock, Blake D; Shaikh, Mohammad F.; Foster, Deshka S.; Piazza, Yelena; Gleeson, Elizabeth M.; Goldstein, Eve; Steele, Lindsay; Campbell, Paul M.; Lin, Bo; Pincus, Matthew R.; Bowne, Wilbur B.

doi:10.21873/anticanres.14749

Cited by 4 publications

(10 citation statements)

References 15 publications

(38 reference statements)

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“…In further studies, PNC-27 and PNC-28 have been found to be cytotoxic to a large variety of human and mammalian solid tissue and non-solid tissue cancer cells, including pancreatic [ 13 ], breast [ 13 ], ovarian [ 14 ], colon [ 15 ], cervical (HeLa) [ 13 ], non-small cell lung carcinoma [ 13 ], angiosarcoma [ 13 ], osteogenic sarcoma [ 13 ], acute myelogenous leukemia [ 16 , 17 ], and chronic myelogenous leukemia [ 18 ], with IC 50 values that ranged from 6–80 μM, while neither peptide was found to be cytotoxic to untransformed control cells that included human fibroblasts [ 13 ], pancreatic acinar cells [ 13 ], human breast epithelial cells [ 13 ], keratinocytes [ 13 ], human umbilical vein (HUVEC) cells [ 14 ], and rat mononuclear cells [ 16 ] at the highest concentrations used with the corresponding cancer cells. Importantly, PNC-28 was found to have no effect on the abilities of human hematopoietic stem cells from the cord blood of five different donors to differentiate into mature hematopoietic cells in the presence of growth factors [ 13 ], strongly suggesting that neither peptide would suppress bone marrow during cancer treatment.…”

Section: Design and Effects Of Pnc-27 And Pnc-28mentioning

confidence: 99%

“…Complete killing of these cells by 60 μM PNC-27 (by not by PNC-29) was achieved after 4 h incubation, suggesting the efficacy of this peptide in the treatment of ovarian cancer. In addition, PNC-27 was found to be cytotoxic to cancer stem cells, including colon cancer cell lines such as CTA, CTR, and SW1222 [ 15 ], that are enriched in CD44-positive tumor stem cells. As discussed below, PNC-27 is cytotoxic to human acute myelogenous tumor stem cells [ 17 ] without affecting normal hematopoietic stem cells [ 13 , 17 ], as discussed above.…”

Section: Design and Effects Of Pnc-27 And Pnc-28mentioning

confidence: 99%

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Poptosis or Peptide-Induced Transmembrane Pore Formation: A Novel Way to Kill Cancer Cells without Affecting Normal Cells

Pincus,

Silberstein,

Zohar

et al. 2024

Biomedicines

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Recent advances in cancer treatment like personalized chemotherapy and immunotherapy are aimed at tumors that meet certain specifications. In this review, we describe a new approach to general cancer treatment, termed peptide-induced poptosis, in which specific peptides, e.g., PNC-27 and its shorter analogue, PNC-28, that contain the segment of the p53 transactivating 12–26 domain that bind to HDM-2 in its 1–109 domain, bind to HDM-2 in the membranes of cancer cells, resulting in transmembrane pore formation and the rapid extrusion of cancer cell contents, i.e., tumor cell necrosis. These peptides cause tumor cell necrosis of a wide variety of solid tissue and hematopoietic tumors but have no effect on the viability and growth of normal cells since they express at most low levels of membrane-bound HDM-2. They have been found to successfully treat a highly metastatic pancreatic tumor as well as stem-cell-enriched human acute myelogenous leukemias in nude mice, with no evidence of off-target effects. These peptides also are cytotoxic to chemotherapy-resistant cancers and to primary tumors. We performed high-resolution scanning immuno-electron microscopy and visualized the pores in cancer cells induced by PNC-27. This peptide forms 1:1 complexes with HDM-2 in a temperature-independent step, followed by dimerization of these complexes to form transmembrane channels in a highly temperature-dependent step parallel to the mode of action of other membranolytic but less specific agents like streptolysin. These peptides therefore may be effective as general anti-cancer agents.

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Section: Design and Effects Of Pnc-27 And Pnc-28mentioning

confidence: 99%

Section: Design and Effects Of Pnc-27 And Pnc-28mentioning

confidence: 99%

Poptosis or Peptide-Induced Transmembrane Pore Formation: A Novel Way to Kill Cancer Cells without Affecting Normal Cells

Pincus,

Silberstein,

Zohar

et al. 2024

Biomedicines

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“…The researchers showed that elevated resistance to paclitaxel, a cytostatic agent combined with nutlin-3a, previously referred to as a P53/MDM2 inhibitor, could be a result of a universal efflux defense mechanism ( 25 ). Interestingly, specific peptides, such as PNC-27, seem to be strong agents implicated in P53/MDM2 inhibition in colon adenocarcinoma, destroying colon carcinoma stem cells by blocking the membrane H/MDM-2 ( 26 ). In conjunction, another study group explored the role of another agent in P53/MDM2 inhibition.…”

Section: P53/mdm2 Alterations In Colon Adenocarcinomamentioning

confidence: 99%

P53/MDM2 Complex-Based Targeted Strategies in Colon Adenocarcinoma

Niotis

Tsiambas

Dimitroulis

et al. 2023

ama

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In the current molecular review, we describe the mechanisms of TP53/MDM2 deregulation and their impact on the colon adenocarcinoma molecular substrate and phenotype. Among the genes that are critically altered in carcinogenesis, the TP53 tumor suppressor gene is of major importance. The TP53 gene (gene locus: 17p13.1) regulates the cell cycle by controlling the G1/S and G2/M checkpoints securing the normal sequence of cell cycle phases. Furthermore, it is involved in apoptosis programmed cell death. The gene is mutated or epigenetically altered in all epithelial malignancies, including colon adenocarcinoma. Additionally, Mouse Double Minute 2 Homolog (MDM2), a proto-oncogene (12q14.3), acts as a major negative regulator for p53 expression in the p53-MDM2 auto-regulatory pathway. MDM2 binds directly to p53 and represses its transcriptional activity, promoting p53 degradation.Conclusion. In colon adenocarcinoma, MDM2 oncogene overexpression directly influences p53 oncoprotein expression levels.

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“…21 The p53 residues in the above peptide when conjugated with a membrane targeting sequence independently bind plasma membrane localized MDM2 leading to necrosis of cancer cells. 22,23 This peptide was named PNC-27 and other p53 residues also showed lesser but signicant anticancer activities. 23 AMPs have been used widely to create both pro-apoptotic and necrotic peptides.…”

Section: Necrotic Peptidesmentioning

confidence: 99%