Abstract
Simple SummaryIn spite of considerable advancements in cancer treatment, there is still a high incidence and mortality of colorectal cancer. The limited effectiveness of current therapies demands innovative and more promising therapeutic strategies. In this study, we therefore examined the potency of a combined therapeutic approach employing magnetic nanoparticles for the induction of magnetic hyperthermia and a 5-fluorouracil-based chemotherapy, termed thermo-chemotherapy. The main objective was to enable the relapse-free eradication of colorectal cancer. In mice models of colorectal cancer, we found successful reduction of the proliferation potential, extensive DNA damage in the treated tumor cells, profound damage to tumor vascular system, and reduced tumor volume, induced by our local combinatorial thermo-chemotherapy. These findings expose potential benefits of the thermo-chemotherapy approach for the effective treatment of colorectal cancer in the future.Magnetic nanoparticles (MNPs) have shown promising features to be utilized in combinatorial magnetic hyperthermia and chemotherapy. Here, we assessed if a thermo-chemotherapeutic approach consisting of the intratumoral application of functionalized chitosan-coated MNPs (CS-MNPs) with 5-fluorouracil (5FU) and magnetic hyperthermia prospectively improves the treatment of colorectal cancer. With utilization of a human colorectal cancer (HT29) heterotopic tumor model in mice, we showed that the thermo-chemotherapeutic treatment is more efficient in inactivating colon cancer than either tumor treatments alone (i.e., magnetic hyperthermia vs. the presence of 5FU attached to MNPs). In particular, the thermo-chemotherapeutic treatment significantly (p < 0.01) impacts tumor volume and tumor cell proliferation (Ki67 expression, p < 0.001) compared to the single therapy modalities. The thermo-chemotherapeutic treatment: (a) affects DNA replication and repair as measured by H2AX and phosphorylated H2AX expression (p < 0.05 to 0.001), (b) it does not distinctly induce apoptosis nor necroptosis in target cells, since expression of p53, PARP cleaved-PARP, caspases and phosphorylated-RIP3 was non-conspicuous, (c) it renders tumor cells surviving therapy more sensitive to further therapy sessions as indicated by an increased expression of p53, reduced expression of NF-κB and HSPs, albeit by tendency with p > 0.05), and (d) that it impacts tumor vascularity (reduced expression of CD31 and αvβ3 integrin (p < 0.01 to 0.001) and consequently nutrient supply to tumors. We further hypothesize that tumor cells die, at least in parts, via a ROS dependent mechanism called oxeiptosis. Taken together, a very effective elimination of colon cancers seems to be feasible by utilization of repeated thermo-chemotherapeutic therapy sessions in the long-term.
Highlights
Colorectal cancer is the third most common and second deadliest cancer worldwide, which led to approximately 881,000 deaths in 2018 [1]
In tumors treated with the combinatorial treatment modality (5FU-Magnetic nanoparticles (MNPs)/magnetic hyperthermia alone (MH)), the in vivo whole-body NIRF-based detection of the endothelial proliferation marker αvβ3 integrin was significantly decreasing with ongoing time after therapy
The unchanged expression of c-PARP after the combinatorial treatment and the either therapies alone, compared to its normal expression in untreated control tumors suggested a low probability of apoptosis as the main known mechanism of cell death. In agreement with this argumentation line, we showed that the expressions of caspase-3, caspase-8 and c-caspase-8, which are known markers of intrinsic and extrinsic apoptosis pathways [47], were unchanged or relatively decreased due to combinatorial tumor treatment compared to the either therapies alone and to the untreated control tumors
Summary
Colorectal cancer is the third most common and second deadliest cancer worldwide, which led to approximately 881,000 deaths in 2018 [1]. These intracellularly active 5FU metabolites inhibit the activity of thymidylate synthase and interfere with RNA and DNA synthesis. A monotherapy of colorectal cancer with 5FU is not highly effective (approximately 10–20% response rates), and an increase in dose would lead to adverse side effects and drug resistance [4]. Further therapeutic strategy developments seem to be urgently needed in order to decrease adverse side effects during treatment
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