A dual-action liposome-peptide formulation synergistically counteracts a gain-of-function p53 mutant
Sneha Ghosh Chaudhary1,2, Swati Bhowmick3, Samriddhi Bhattacharya1
1Infectious Diseases and Immunology, CSIR - Indian Institute of Chemical Biology, Kolkata, India.
Abstract:
Inactivation of p53 tumor suppressor functions, often through missense mutations, is essential for carcinogenesis. A sub-class of such p53 missense mutations gains new functions, including drug resistance and enhanced proliferation, in addition to its loss of function. Among the most frequent gain-of-function p53 mutants, R273H occurs in tumors of many tissue origins and imparts aggressive character and resistance to drugs to the tumor. Tumors bearing p53R273H are generally resistant to all available therapies, and need for novel interventions are urgently needed. Interaction of p53R273H with Positive Coactivator 4 (PC4), an abundant chromatin-associated protein, is essential for acquiring the gain-of-function properties. Previously, we developed a chemically modified peptide, NLS-p53(380-386), targeting PC4 that abrogated the interaction of p53R273H with PC4 and reversed many of its gain-of-function properties. We earlier demonstrated that cationic phosphatidylcholine-stearylamine (PC-SA) liposomes possess inherent anti-tumor properties. To improve efficacy, pharmacokinetics, and delivery, we entrapped the PC4-targeted peptide into PC-SA liposome. We synthesized the NLS-p53(380-386) peptide and entrapped in PC-SA liposome. We used MTT assay, confocal microscopy, flow cytometry, qRT-PCR, and western blotting to investigate the biological effects of the p53-entrapped PC-SA. Pretreatment with the PC-SA liposome entrapped peptide enhanced the chemosensitivity of widely used anticancer drug doxorubicin in cell lines bearing p53R273H mutation. The doxorubicin-induced cell-killing effect was much more enhanced when pretreated with the liposome-entrapped peptide than when pretreated with either the free peptide or the liposome alone. The liposome-encapsulated peptide is a promising formulation for developing therapies targeting tumors bearing the p53R273H.
Insights
Targeting the gain-of-function p53R273H mutation with a PC4-targeted peptide encapsulated in liposomes enhances doxorubicin chemotherapy. This novel formulation shows promise for treating resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Delivery
Background:
- Gain-of-function p53 mutations, like R273H, drive cancer by conferring drug resistance and promoting proliferation.
- The p53R273H mutant interacts with Positive Coactivator 4 (PC4), a key factor in its oncogenic properties.
- Current therapies are ineffective against p53R273H-driven tumors, necessitating novel treatment strategies.
Purpose of the Study:
- To develop and evaluate a novel drug delivery system for targeting p53R273H gain-of-function mutations.
- To investigate the efficacy of a PC4-targeted peptide encapsulated in cationic liposomes (PC-SA) in combination with doxorubicin.
Main Methods:
- Synthesis of NLS-p53(380-386) peptide and its encapsulation into PC-SA liposomes.
- Utilized MTT assays, confocal microscopy, flow cytometry, qRT-PCR, and Western blotting to assess biological effects.
- Evaluated the impact of the liposomal peptide formulation on doxorubicin chemosensitivity in p53R273H-mutant cancer cell lines.
Main Results:
- The liposome-encapsulated NLS-p53(380-386) peptide significantly enhanced doxorubicin's cancer cell-killing effect.
- Pretreatment with the liposomal peptide formulation was more effective than free peptide or liposomes alone.
- The formulation demonstrated improved efficacy in enhancing chemosensitivity for p53R273H-mutant cells.
Conclusions:
- Liposome-encapsulated PC4-targeted peptide is a promising strategy to overcome drug resistance in p53R273H-mutant cancers.
- This formulation represents a potential therapeutic approach for aggressive tumors harboring the p53R273H mutation.
- Further development of this liposomal peptide delivery system could lead to improved cancer therapies.
