Carfilzomib promotes the unfolded protein response and apoptosis in cetuximab-resistant colorectal cancer
- Authors: Zulkifli, Ahmad , Tan, Fiona , Areeb, Zammam , Stuart, Sarah , Luwor, Rodney
- Date: 2021
- Type: Text , Journal article
- Relation: International Journal of Molecular Sciences Vol. 22, no. 13 (2021), p.
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- Description: Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Rodney Luwor” is provided in this record**
Paclitaxel-loaded self-assembled lipid nanoparticles as targeted drug delivery systems for the treatment of aggressive ovarian cancer
- Authors: Zhai, Jiali , Luwor, Rodney , Ahmed, Nuzhat , Escalona, Ruth , Tan, Fiona , Fong, Celesta , Ratcliffe, Julian , Scoble, Judith , Drummond, Calum , Tran, Nhiem
- Date: 2018
- Type: Text , Journal article
- Relation: ACS Applied Materials & Interfaces Vol. 10, no. 30 (2018), p. 25174-25185
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- Description: Chemotherapy using cytotoxic agents, such as paclitaxel (PTX), is one of the most effective treatments for advanced ovarian cancer. However, due to nonspecific targeting of the drug and the presence of toxic solvents required for dissolving PTX prior to injection, there are several serious side effects associated with this treatment. In this study, we explored self-assembled lipid-based nanoparticles as PTX carriers, which were able to improve its antitumour efficacy against ovarian cancer. The nanoparticles were also functionalized with epidermal growth factor receptor (EGFR) antibody fragments to explore the benefit of tumor active targeting. The formulated bicontinuous cubic- and sponge-phase nanoparticles, which were stabilized by Pluronic F127 and a lipid poly(ethylene glycol) stabilizer, showed a high capacity of PTX loading. These PTX-loaded nanoparticles also showed significantly higher cytotoxicity than a free drug formulation against HEY ovarian cancer cell lines in vitro. More importantly, the nanoparticle-based PTX treatments, with or without EGFR targeting, reduced the tumor burden by 50% compared to PTX or nondrug control in an ovarian cancer mouse xenograft model. In addition, the PTX-loaded nanoparticles were able to extend the survival of the treatment groups by up to 10 days compared to groups receiving free PTX or nondrug control. This proof-of-concept study has demonstrated the potential of these self-assembled lipid nanomaterials as effective drug delivery nanocarriers for poorly soluble chemotherapeutics, such as PTX.
In vitro and in vivo toxicity and biodistribution of paclitaxel-loaded cubosomes as a drug delivery nanocarrier : a case study using an A431 skin cancer xenograft model
- Authors: Zhai, Jiali , Tan, Fiona , Luwor, Rodney , Srinivasa Reddy, T. , Ahmed, Nuzhat , Drummond, Calum , Tran, Nhiem
- Date: 2020
- Type: Text , Journal article
- Relation: ACS Applied Bio Materials Vol. 3, no. 7 (2020), p. 4198-4207
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- Description: Cubosomes with an internal three-dimensional (3D) periodic and porous particulate nanostructure have emerged as a promising drug delivery system for hydrophobic small molecules as well as large biomolecules over the past several decades. Limited understanding of their safety profiles and biodistribution, however, hinders clinical translation. This study used monoolein-based cubosomes stabilized by Pluronic F127 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)] polymers to encapsulate paclitaxel (PTX) as a model drug and investigated the in vitro cytotoxicity, in vivo acute response, and whole body biodistribution of the developed nanoparticles. Comparison of the PTX and nanoparticle cytotoxicity in two-dimensional and 3D spheroid cell models revealed distinct differences, with the cells in the 3D model found to be more tolerable to unloaded PTX as well as the PTX-loaded nanoparticle form. One-time intraperitoneal (i.p.) injection of unloaded cubosomes were generally well tolerated up to 400 mg/kg. Using the A431 skin cancer xenograft model, in vivo imaging studies showed the preferential accumulation of PTX-loaded cubosomes at the tumor sites following i.p. injection. Lastly, average tumor size was reduced by approximately 50% in the nanoparticle-based treatment group compared to the unloaded PTX drug group. The study provides significant information on the biological response of cubosomes and highlights their potential as a versatile drug delivery platform for safe and effective delivery of chemotherapeutic drugs. © 2020 American Chemical Society.
- Description: The authors acknowledge the Capability Development Fund Scheme of RMIT University, the Maxwell Eagle Endowment Award and the CASS Foundation Science/Medicine Grant for financial support. N.T. is a recipient of an RMIT Vice-Chancellor’s Research Fellowship.