Dataset Information

Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation.

ABSTRACT: The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell-penetrating capabilities.Encapsulation of the MUC1-C inhibitor GO-203 in novel polymeric nanoparticles was studied for effects on intracellular targeting of MUC1-C signaling and function.Our results show that loading GO-203 into tetrablock polylactic acid (PLA)-polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG copolymers is achievable and, notably, is enhanced by increasing PEG chain length. In addition, we found that release of GO-203 from these nanoparticles is controllable over at least 7 days. GO-203/nanoparticle treatment of MUC1-C-positive breast and lung cancer cells in vitro was more active with less frequent dosing than that achieved with nonencapsulated GO-203. Moreover, treatment with GO-203/nanoparticles blocked MUC1-C homodimerization, consistent with on-target effects. GO-203/nanoparticle treatment was also effective in downregulating TIGAR, disrupting redox balance, and inhibiting the self-renewal capacity of cancer cells. Significantly, weekly administration of GO-203/nanoparticles to mice bearing syngeneic or xenograft tumors was associated with regressions that were comparable with those found when dosing on a daily basis with GO-203.These findings thus define an effective approach for (i) sustained administration of GO-203 in polymeric PLA-(PEG-PPG-PEG) nanoparticles to target MUC1-C in cancer cells and (ii) the potential delivery of other anticancer peptide drugs.

SUBMITTER: Hasegawa M

PROVIDER: S-EPMC4433879 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation.

Hasegawa Masanori M Sinha Raj Kumar RK Kumar Manoj M Alam Maroof M Yin Li L Raina Deepak D Kharbanda Akriti A Panchamoorthy Govind G Gupta Dikshi D Singh Harpal H Kharbanda Surender S Kufe Donald D

Clinical cancer research : an official journal of the American Association for Cancer Research 20150223 10

<h4>Purpose</h4>The MUC1-C oncoprotein is an intracellular target that is druggable with cell-penetrating peptide inhibitors. However, development of peptidyl drugs for treating cancer has been a challenge because of unfavorable pharmacokinetic parameters and limited cell-penetrating capabilities.<h4>Experimental design</h4>Encapsulation of the MUC1-C inhibitor GO-203 in novel polymeric nanoparticles was studied for effects on intracellular targeting of MUC1-C signaling and function.<h4>Results< ...[more]

PMID: 25712682

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Project description:Cancer is a multifactorial disease necessitating identification of novel targets for its treatment. Inhibition of Bcl-2 for triggered pro-apoptotic signaling is considered a promising strategy for cancer treatment. Within the current work, we aimed to design and synthesize a new series of benzimidazole- and indole-based derivatives as inhibitors of Bcl-2 protein. The market pan-Bcl-2 inhibitor, obatoclax, was the lead framework compound for adopted structural modifications. The obatoclax's pyrrolylmethine linker was replaced with straight alkylamine or carboxyhydrazine methylene linkers providing the new compounds. This strategy permitted improved structural flexibility of synthesized compounds adopting favored maneuvers for better fitting at the Bcl-2 major hydrophobic pocket. Anti-cancer activity of the synthesized compounds was further investigated through MTT-cytotoxic assay, cell cycle analysis, RT-PCR, ELISA and DNA fragmentation. Cytotoxic results showed compounds 8a, 8b and 8c with promising cytotoxicity against MDA-MB-231/breast cancer cells (IC50 = 12.69 ± 0.84 to 12.83 ± 3.50 µM), while 8a and 8c depicted noticeable activities against A549/lung adenocarcinoma cells (IC50 = 23.05 ± 1.45 and 11.63 ± 2.57 µM, respectively). The signaling Bcl-2 inhibition pathway was confirmed by molecular docking where significant docking energies and interactions with key Bcl-2 pocket residues were depicted. Moreover, the top active compound, 8b, showed significant upregulated expression levels of pro-apoptotic/anti-apoptotic of genes; Bax, Bcl-2, caspase-3, -8, and -9 through RT-PCR assay. Improving the compound's pharmaceutical profile was undertaken by introducing 8b within drug-solid/lipid nanoparticle formulation prepared by hot melting homogenization technique and evaluated for encapsulation efficiency, particle size, and zeta potential. Significant improvement was seen at the compound's cytotoxic activity. In conclusion, 8b is introduced as a promising anti-cancer lead candidate that worth future fine-tuned lead optimization and development studies while exploring its potentiality through in-vivo preclinical investigation.

Dataset Information

Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation.

Publications

Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation.

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