scholarly journals Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

2021 ◽  
Author(s):  
Boah Lee ◽  
Seung Ju Park ◽  
Seulgi Lee ◽  
Jinwook Lee ◽  
Eun Byeol Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Therapeutic Option ◽  
Cholesterol Lowering ◽  
Cellular Environment ◽  
Lowering Drug

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC-38 or B16-F10 pre-clinical syngeneic tumor models. These results elucidates the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.

Fisetin mediated apoptotic cell death in parental and Oxaliplatin/irinotecan resistant colorectal cancer cells in vitro and in vivo

2018 ◽  
Vol 233 (9) ◽  
pp. 7134-7142 ◽  
Author(s):  
Long-Bin Jeng ◽  
Bharath Kumar Velmurugan ◽  
Ming-Cheng Chen ◽  
Hsi-Hsien Hsu ◽  
Tsung-Jung Ho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Colorectal Cancer Cells

scholarly journals In Vitro Examinations of Cell Death Induction and the Immune Phenotype of Cancer Cells Following Radiative-Based Hyperthermia with 915 MHz in Combination with Radiotherapy

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1436
Author(s):  
Michael Hader ◽  
Simon Streit ◽  
Andreas Rosin ◽  
Thorsten Gerdes ◽  
Martin Wadepohl ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Major Influence ◽  
Frequency Dependent ◽  
Immune Phenotype ◽  
Mcf 7

Multimodal tumor treatment settings consisting of radiotherapy and immunomodulating agents such as immune checkpoint inhibitors are more and more commonly applied in clinics. In this context, the immune phenotype of tumor cells has a major influence on the anti-tumor immune response as well as the composition of the tumor microenvironment. A promising approach to further boost anti-tumor immune responses is to add hyperthermia (HT), i.e., heating the tumor tissue between 39 °C to 45 °C for 60 min. One key technique is the use of radiative hyperthermia systems. However, knowledge is limited as to how the frequency of the used radiative systems affects the immune phenotype of the treated tumor cells. By using our self-designed in vitro hyperthermia system, we compared cell death induction and expression of immune checkpoint molecules (ICM) on the tumor cell surface of murine B16 melanoma and human MDA-MB-231 and MCF-7 breast cancer cells following HT treatment with clinically relevant microwaves at 915 MHz or 2.45 GHz alone, radiotherapy (RT; 2 × 5 Gy or 5 × 2 Gy) alone or in combination (RHT). At 44 °C, HT alone was the dominant cell death inductor with inactivation rates of around 70% for B16, 45% for MDA‑MB‑231 and 35% for MCF-7 at 915 MHz and 80%, 60% and 50% at 2.45 GHz, respectively. Additional RT resulted in 5–15% higher levels of dead cells. The expression of ICM on tumor cells showed time-, treatment-, cell line- and frequency-dependent effects and was highest for RHT. Computer simulations of an exemplary spherical cell revealed frequency-dependent local energy absorption. The frequency of hyperthermia systems is a newly identified parameter that could also affect the immune phenotype of tumor cells and consequently the immunogenicity of tumors.

scholarly journals Arginine Deiminase Induces Immunogenic Cell Death and Is Enhanced by N-acetylcysteine in Murine MC38 Colorectal Cancer Cells and MDA-MB-231 Human Breast Cancer Cells In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 511
Author(s):  
Zhiying Huang ◽  
Haifeng Hu
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
High Mobility ◽  
Arginine Deiminase ◽  
Immunogenic Cell Death ◽  
Anticancer Properties ◽  
Colorectal Cancer Cells ◽  
First Time

The use of arginine deiminase (ADI) for arginine depletion therapy is an attractive anticancer approach. Combination strategies are needed to overcome the resistance of severe types of cancer cells to this monotherapy. In the current study, we report, for the first time, that the antioxidant N-acetylcysteine (NAC), which has been used in therapeutic practices for several decades, is a potent enhancer for targeted therapy that utilizes arginine deiminase. We demonstrated that pegylated arginine deiminase (ADI-PEG 20) induces apoptosis and G0/G1 phase arrest in murine MC38 colorectal cancer cells; ADI-PEG 20 induces Ca2+ overload and decreases the mitochondrial membrane potential in MC38 cells. ADI-PEG 20 induced the most important immunogenic cell death (ICD)-associated feature: cell surface exposure of calreticulin (CRT). The antioxidant NAC enhanced the antitumor activity of ADI-PEG 20 and strengthened its ICD-associated features including the secretion of high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). In addition, these regimens resulted in phagocytosis of treated MC38 cancer cells by bone marrow-derived dendritic cells (BMDCs). In conclusion, we describe, for the first time, that NAC in combination with ADI-PEG 20 not only possesses unique cytotoxic anticancer properties but also triggers the hallmarks of immunogenic cell death. Hence, ADI-PEG 20 in combination with NAC may represent a promising approach to treat ADI-sensitive tumors while preventing relapse and metastasis.

scholarly journals Schizandrin A exhibits potent anticancer activity in colorectal cancer cells by inhibiting heat shock factor 1

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Bing-chen Chen ◽  
Shi-liang Tu ◽  
Bo-an Zheng ◽  
Quan-jin Dong ◽  
Zi-ang Wan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Heat Shock ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Hydrophobic Interactions ◽  
Heat Shock Factor ◽  
Luciferase Reporter ◽  
Heat Shock Factor 1

Abstract Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.

scholarly journals Multiorganelle Localization of Metallated Phthalocyanine Photosensitizer in Colorectal Cancer Cells (DLD-1 and CaCo-2) Enhances Efficacy of Photodynamic Therapy

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Palesa Rose Sekhejane ◽  
Nicolette Nadene Houreld ◽  
Heidi Abrahamse
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Annexin V ◽  
Zinc Phthalocyanine ◽  
Cell Death Pathway

Colorectal cancer is the third most commonly diagnosed cancer. Amongst treatments that have been explored, photodynamic therapy (PDT) is a treatment that is of interest as it poses ideal advantages such as affinity for cancer cells. This study aimed to determine the correlation between the localization site of a sulfonated zinc phthalocyanine (ZnPcSmix) photosensitizer (PS) and its associated cell death pathwayin vitroin colorectal cancer cell lines (DLD-1 and CaCo-2). Visible morphological changes were observed in PDT treated cells after 24 h. Reactive oxygen species (ROS) were detected and visualized 1 h after PDT.ZnPcSmixwas predominantly localized in lysosomes and partially in the mitochondria. FITC Annexin V staining showed a significant decrease in the percentage of viable DLD-1 and CaCo-2 cells 24 h after PDT, with an increase in apoptotic cell population. Moreover, there was a significant increase in both cathepsin D and cytochrome C at 1 and 24 h. In conclusion,ZnPcSmixshowed the ability of inducing apoptotic cell death features in PDT treated cells.

scholarly journals Beyond Cell Death – Antiapoptotic Bcl-2 Proteins Regulate Migration and Invasion of Colorectal Cancer Cells In Vitro

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e76446 ◽  
Author(s):  
Bruno Christian Koehler ◽  
Anna-Lena Scherr ◽  
Stephan Lorenz ◽  
Toni Urbanik ◽  
Nicole Kautz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Migration And Invasion ◽  
Colorectal Cancer Cells

scholarly journals Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo

Autophagy ◽  
2018 ◽  
Vol 15 (2) ◽  
pp. 295-311 ◽  
Author(s):  
Yuanyuan Fu ◽  
Liang Hong ◽  
Jiecheng Xu ◽  
Guoping Zhong ◽  
Qiong Gu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Small Molecule ◽  
Colorectal Cancer Cells

scholarly journals 5-Fluorouracil Encapsulated Chitosan-Cellulose Fiber Bionanocomposites: Synthesis, Characterization and In Vitro Analysis towards Colorectal Cancer Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1691
Author(s):  
Mostafa Yusefi ◽  
Hui-Yin Chan ◽  
Sin-Yeang Teow ◽  
Pooneh Kia ◽  
Michiele Lee-Kiun Soon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Sodium Tripolyphosphate ◽  
Chitosan Nanoparticles ◽  
Cellulose Fiber ◽  
In Vitro Cytotoxicity ◽  
Layer By Layer ◽  
Normal Cells

Cellulose and chitosan with remarkable biocompatibility and sophisticated physiochemical characteristics can be a new dawn to the advanced drug nano-carriers in cancer treatment. This study aims to synthesize layer-by-layer bionanocomposites from chitosan and rice straw cellulose encapsulated 5-Fluorouracil (CS-CF/5FU BNCs) using the ionic gelation method and the sodium tripolyphosphate (TPP) cross-linker. Data from X-ray and Fourier-transform infrared spectroscopy showed successful preparation of CS-CF/5FU BNCs. Based on images of scanning electron microscopy, 48.73 ± 1.52 nm was estimated for an average size of the bionanocomposites as spherical chitosan nanoparticles mostly coated rod-shaped cellulose reinforcement. 5-Fluorouracil indicated an increase in thermal stability after its encapsulation in the bionanocomposites. The drug encapsulation efficiency was found to be 86 ± 2.75%. CS-CF/5FU BNCs triggered higher drug release in a media simulating the colorectal fluid with pH 7.4 (76.82 ± 1.29%) than the gastric fluid with pH 1.2 (42.37 ± 0.43%). In in vitro cytotoxicity assays, cellulose fibers, chitosan nanoparticles and the bionanocomposites indicated biocompatibility towards CCD112 normal cells. Most promisingly, CS-CF/5FU BNCs at 250 µg/mL concentration eliminated 56.42 ± 0.41% of HCT116 cancer cells and only 8.16 ± 2.11% of CCD112 normal cells. Therefore, this study demonstrates that CS-CF/5FU BNCs can be considered as an eco-friendly and innovative nanodrug candidate for potential colorectal cancer treatment.

scholarly journals Pals1 prevents Rac1-dependent colorectal cancer cell metastasis by inhibiting Arf6

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Simona Mareike Lüttgenau ◽  
Christin Emming ◽  
Thomas Wagner ◽  
Julia Harms ◽  
Justine Guske ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Scaffolding Protein ◽  
Migration And Invasion ◽  
Tight Junction Formation ◽  
Cell Metastasis ◽  
Colorectal Cancer Cells

AbstractLoss of apical-basal polarity and downregulation of cell-cell contacts is a critical step during the pathogenesis of cancer. Both processes are regulated by the scaffolding protein Pals1, however, it is unclear whether the expression of Pals1 is affected in cancer cells and whether Pals1 is implicated in the pathogenesis of the disease.Using mRNA expression data and immunostainings of cancer specimen, we show that Pals1 is frequently downregulated in colorectal cancer, correlating with poorer survival of patients. We further found that Pals1 prevents cancer cell metastasis by controlling Rac1-dependent cell migration through inhibition of Arf6, which is independent of the canonical binding partners of Pals1. Loss of Pals1 in colorectal cancer cells results in increased Arf6 and Rac1 activity, enhanced cell migration and invasion in vitro and increased metastasis of transplanted tumor cells in mice. Thus, our data reveal a new function of Pals1 as a key inhibitor of cell migration and metastasis of colorectal cancer cells. Notably, this new function is independent of the known role of Pals1 in tight junction formation and apical-basal polarity.

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