MCP mediated active targeting calcium phosphate hybrid nanoparticles for the treatment of orthotopic drug-resistant colon cancer

Abstract Background Colon cancer is a most common malignant cancer in digestive system, and it is prone to develop resistance to the commonly used chemotherapy drugs, leading to local recurrence and metastasis. Paris saponin VII (PSVII) could not only inhibit the proliferation of colon cancer cells but also effectively induce apoptosis of drug-resistant colon cancer cells and reduce the metastasis of drug-resistant colon cancer cells as well. However, PSVII was insoluble in water and fat. It displayed no selective distribution in body and could cause severe hemolysis. Herein, colon cancer targeting calcium phosphate nanoparticles were developed to carry PSVII to treat drug-resistant colon cancer. Results PSVII carboxymethyl-β-cyclodextrin inclusion compound was successfully encapsulated in colon cancer targeting calcium phosphate nanoparticles (PSVII@MCP-CaP) by using modified citrus pectin as stabilizer agent and colon cancer cell targeting moiety. PSVII@MCP-CaP significantly reduced the hemolysis of PSVII. Moreover, by specific accumulating in orthotopic drug-resistant colon cancer tissue, PSVII@MCP-CaP markedly inhibited the growth of orthotopic drug-resistant colon cancer in nude mice. PSVII@MCP-CaP promoted the apoptosis of drug-resistant colon cancer cells through mitochondria-mediated apoptosis pathway. Moreover, PSVII@MCP-CaP significantly inhibited the invasion and migration of drug-resistant colon cancer cells by increasing E-cadherin protein expression and reducing N-cadherin and MMP-9 protein expression. Conclusion PSVII@MCP-CaP has great potential in the treatment of drug-resistant colon cancer. This study also explores a new method to prepare active targeting calcium phosphate nanoparticles loaded with a fat and water insoluble compound in water. Graphical Abstract

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Anti-ROR1 functionalised PLGA nanoparticles modulate metastatic and EMT biomarkers via cellular uptake of curcumin and ICA in colon cancer cells SW480

10.22541/au.160607382.21716239/v1 ◽

2020 ◽

Author(s):

Shamim Sufi ◽

Muddasarul Hoda ◽

Sankar Pajaniradje ◽

Victor Mukherjee ◽

Sultana Parveen ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Cellular Uptake ◽

Isothermal Calorimetry ◽

Cell Surface Receptor ◽

In Vivo Studies ◽

Active Targeting ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

Surface Functionalisation

The challenge of next-generation nanoparticles (NPs) includes limited cellular uptake and loss by phagocytosis. General surface modification of NPs potentially enhances evasion from phagocytosis. However, active targeting and enhanced cellular uptake of nanoparticles are possible by surface functionalisation with molecules that have selective affinity for cancer cells. ROR1 is a cell surface receptor that is over-expressed in cancer cells. Hence, its conjugate antibody could be a potential surface functionalisation molecule. In the current study, anti-ROR1 antibody has been covalently attached to nanoparticles’ surface, thereby imparting its active targeting potential. Physicochemical and in vitro characterisations of the antibody-conjugated nanoparticles were performed. Surface functionalisation of nanoparticles was confirmed by scanning electron microscopy, isothermal calorimetry, and elemental analysis. Additionally, biomarkers of metastasis and epithelial-mesenchymal transition (EMT) were studied. Anti-ROR1 mAb tagged nanoparticles further confirmed therapeutic efficacy against colon cancer cells, SW480, thus, opening scope for further in vivo studies.

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Protein expression following γ-irradiation relevant to growth arrest and apoptosis in colon cancer cells

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-009-0606-4 ◽

2009 ◽

Vol 135 (11) ◽

pp. 1583-1592 ◽

Cited By ~ 14

Author(s):

Daniella Pfeifer ◽

Åsa Wallin ◽

Birgitta Holmlund ◽

Xiao-Feng Sun

Keyword(s):

Colon Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Growth Arrest ◽

Colon Cancer Cells ◽

Γ Irradiation

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Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant

Cell Death and Disease ◽

10.1038/s41419-020-03232-z ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Michael Fichtner ◽

Emir Bozkurt ◽

Manuela Salvucci ◽

Christopher McCann ◽

Katherine A. McAllister ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Caspase 8 ◽

Colon Cancer Cells ◽

Apoptosis Pathway ◽

Iap Antagonist

AbstractColorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.

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GLUT5 regulation by AKT1/3-miR-125b-5p downregulation induces migratory activity and drug resistance in TLR-modified colorectal cancer cells

Carcinogenesis ◽

10.1093/carcin/bgaa074 ◽

2020 ◽

Vol 41 (10) ◽

pp. 1329-1340 ◽

Cited By ~ 1

Author(s):

Ga-Bin Park ◽

Jee-Yeong Jeong ◽

Daejin Kim

Keyword(s):

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Cell Metabolism ◽

Enzyme Activation ◽

Migration And Invasion ◽

Drug Resistant ◽

Cancer Resistance ◽

Colon Cancer Cells ◽

Migratory Activity

Abstract In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development.

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Regulation of major vault protein expression by upstream stimulating factor 1 in SW620 human colon cancer cells

Oncology Reports ◽

10.3892/or.2013.2818 ◽

2013 ◽

Vol 31 (1) ◽

pp. 197-201 ◽

Cited By ~ 4

Author(s):

RYUJI IKEDA ◽

YUKIHIKO NISHIZAWA ◽

YUSUKE TAJITSU ◽

KENTARO MINAMI ◽

HIRONORI MATAKI ◽

...

Keyword(s):

Colon Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Human Colon ◽

Major Vault Protein ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Human Colon Cancer Cells ◽

Stimulating Factor

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Prooxidative Activity of Celastrol Induces Apoptosis, DNA Damage, and Cell Cycle Arrest in Drug-Resistant Human Colon Cancer Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6793957 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 6

Author(s):

Helena Moreira ◽

Anna Szyjka ◽

Kamila Paliszkiewicz ◽

Ewa Barg

Keyword(s):

Cell Cycle ◽

Colon Cancer ◽

Cell Death ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Phase Cell ◽

Drug Resistant ◽

Cancer Resistance ◽

Colon Cancer Cells ◽

Cycle Arrest

Cancer resistance to chemotherapy is closely related to tumor heterogeneity, i.e., the existence of distinct subpopulations of cancer cells in a tumor mass. An important role is assigned to cancer stem cells (CSCs), a small subset of cancer cells with high tumorigenic potential and capacity of self-renewal and differentiation. These properties of CSCs are sustained by the ability of those cells to maintain a low intracellular reactive oxygen species (ROS) levels, via upregulation of ROS scavenging systems. However, the accumulation of ROS over a critical threshold disturbs CSCs—redox homeostasis causing severe cytotoxic consequences. In the present study, we investigated the capacity of celastrol, a natural pentacyclic triterpenoid, to induce the formation of ROS and, consequently, cell death of the colon cancer cells with acquired resistant to cytotoxic drugs (LOVO/DX cell line). LOVO/DX cells express several important stem-like cell features, including a higher frequency of side population (SP) cells, higher expression of multidrug resistant proteins, overexpression of CSC-specific cell surface marker (CD44), increased expression of DNA repair gene (PARP1), and low intracellular ROS level. We found that celastrol, at higher concentrations (above 1 μM), significantly increased ROS amount in LOVO/DX cells at both cytoplasmic and mitochondrial levels. This prooxidant activity was associated with the induction of DNA double-strand breaks (DSBs) and apoptotic/necrotic cell death, as well as with inhibition of cell proliferation by S phase cell cycle arrest. Coincubation with NAC, a ROS scavenger, completely reversed the above effects. In summary, our results provide evidence that celastrol exhibits effective cytotoxic effects via ROS-dependent mechanisms on drug-resistant colon cancer cells. These findings strongly suggest the potential of celastrol to effectively kill cancer stem-like cells, and thus, it is a promising agent to treat severe, resistant to conventional therapy, colon cancers.

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Patient-Derived, Drug-Resistant Colon Cancer Cells Evade Chemotherapeutic Drug Effects via the Induction of Epithelial-Mesenchymal Transition-Mediated Angiogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms21207469 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7469 ◽

Cited By ~ 1

Author(s):

Jin Hong Lim ◽

Kyung Hwa Choi ◽

Soo Young Kim ◽

Cheong Soo Park ◽

Seok-Mo Kim ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Xenograft Model ◽

Drug Effects ◽

Control Group ◽

Metastatic Colon Cancer ◽

Drug Resistant ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

Mouse Xenograft Model

Cancer cells can exhibit resistance to different anticancer drugs by acquiring enhanced anti-apoptotic potential, improved DNA injury resistance, diminished enzymatic inactivation, and enhanced permeability, allowing for cell survival. However, the genetic mechanisms for these effects are unknown. Therefore, in this study, we obtained drug-sensitive HT-29 cells (commercially) and drug-resistant cancer cells (derived from biochemically and histologically confirmed colon cancer patients) and performed microarray analysis to identify genetic differences. Cellular proliferation and other properties were determined after treatment with oxaliplatin, lenvatinib, or their combination. In vivo, tumor volume and other properties were examined using a mouse xenograft model. The oxaliplatin and lenvatinib cotreatment group showed more significant cell cycle arrest than the control group and groups treated with either agent alone. Oxaliplatin and lenvatinib cotreatment induced the most significant tumor shrinkage in the xenograft model. Drug-resistant and metastatic colon cancer cells evaded the anticancer drug effects via angiogenesis. These findings present a breakthrough strategy for treating drug-resistant cancer.

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