A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera
| Autor: | Ruben C. Aguilar, Mike Lu, Swetha Ramadesikan, Nicholas L. Truex, Erin M. Kischuk, Andrew J. McCluskey, John Collier, Bradley L. Pentelute, Hristos Z. Kaimakliotis, Timothy L. Ratliff, Sneha Subramanian, Michael S. Santos, Deborah W. Knapp, Sherwin Jack, Bennett D. Elzey, Alexander R. Loftis, Amy E. Rabideau, Deepika Dhawan, Kayalvizhi Madhivanan, Michael O. Koch, Daniel F. Edwards |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Cancer Research Programmed cell death Receptor ErbB-2 Anthrax toxin Bacterial Toxins Primary Cell Culture Antineoplastic Agents Apoptosis Article 03 medical and health sciences Mice 0302 clinical medicine Dogs In vivo Cell Line Tumor Medicine Animals Humans Antigens Bacterial Bladder cancer Epidermal Growth Factor business.industry Immunotoxins medicine.disease In vitro Administration Intravesical Treatment Outcome Oncology Urinary Bladder Neoplasms 030220 oncology & carcinogenesis Cancer cell Toxicity Cancer research Female Drug Screening Assays Antitumor business |
| Zdroj: | Int J Cancer |
| Popis: | Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC(50) < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF–anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer. |
| Databáze: | OpenAIRE |
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