Abstract
In this study we looked for the main protein pathway regulators which were responsible for the therapeutic impact on colon cancers when combining magnetic hyperthermia with the chemotherapeutic agent 5-fluorouracil (5FU). To this end, chitosan-coated magnetic nanoparticles (MNP) functionalized with 5FU were intratumorally injected into subcutaneous human colon cancer xenografts (HT-29) in mice and exposed to an alternating magnetic field. A decreased tumor growth was found particularly for the combined thermo-chemotherapy vs. the corresponding monotherapies. By using computational analysis of the tumor proteome, we found upregulated functional pathway categories termed “cellular stress and injury”, “intracellular second messenger and nuclear receptor signaling”, “immune responses”, and “growth proliferation and development”. We predict TGF-beta, and other mediators, as important upstream regulators. In conclusion, our findings show that the combined thermo-chemotherapy induces thrombogenic collagen fibers which are able to impair tumor nutrient supply. Further on, we associate several responses to the recognition of damage associated molecular patterns (DAMPs) by phagocytic cells, which immigrate into the tumor area. The activation of some pathways associated with cell survival implies the necessity to conduct multiple therapy sessions in connection with a corresponding monitoring, which could possibly be performed on the base of the identified protein regulators.
Highlights
Along with the increasing number of cancers worldwide, colon cancer has always been one of the most common types
We found a distinct impact on the tumor extracellular matrix, the induction of thrombogenic collagen fibers, a distinct impact on second messenger, and nuclear receptor signaling as a response to cellular stress in relation to the combined thermo-chemotherapy
Nanoparticle coating with chitosan was performed by chemisorption and excess of chitosan was removed by several washing steps. 5-fluorouracil (5FU) powder was obtained from Sigma-Aldrich
Summary
Along with the increasing number of cancers worldwide, colon cancer has always been one of the most common types. In 2020, more than 1.1 million new cases were estimated to be diagnosed [1]. Cost-effective and minimally invasive techniques such as colonoscopy and fecal immunohistochemistry have contributed to the early diagnosis of this cancer [2]. The surgical removal of precursor lesions following early diagnosis, as well as improvements in adjuvant therapies, including radiotherapy and chemotherapy, have increased survival rates of this cancer type [3]. Despite significant progress in screening and treatment, colon cancer was estimated to cause more than 0.5 million deaths in 2020 [1]. Great emphasis has been devoted to the development of nanomedicines for the treatment of cancers. The utilization of iron-oxide nanoparticles allows the exploitation of the magnetic core for heat-mediated cell inactivation purposes, termed
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