Sulfonamide-Functionalized Polymeric Nanoparticles For Enhanced In Vivo Colorectal Cancer Therapy

Background: Colorectal cancer (CRC) is the third most common cancer in the world. 5-Fluorouracil (5-FU) is a conventional and most effective drug used in the clinic for the treatment of CRC. However, the clinical use of 5-FU is limited due to the acquired resistance and systemic toxicity, such as hepatotoxicity and gastrointesti-nal toxicity. Objective: Recent advances in nanomedicine are being exploited to develop nanoparticle platforms to overcome resistance and therapeutic delivery of active molecules. Here, we develop 5-FU loaded sulfadiazine-poly(lactide-co-glycolide) nanoparticles (SUL-PLGA NPs) to be applied in the colorectal cancer model. Methods: We assessed the in vivo efficacy of the SUL-PLGA NPs to enhance the antitumor effect of 5-FU. Results: In vivo treatment with 5-FU-SUL-PLGA NPs significantly reduced tumor growth in a colon cancer xen-ograft model compared to free 5-FU and 5-FU loaded non-targeted NPs. Treatment with 5-FU-SUL-PLGA NPs also increased blood vessel diameters within tumors, which could act in conjunction to enhance antitumor effi-cacy. In addition, 5-FU-SUL-PLGA NPs significantly reduced liver mass and lung mass, which are the most common metastasis sites of CRC, and decreased liver hepatotoxicity compared to free 5-FU drug and 5-FU loaded non-targeted NPs. Conclusion: Our findings suggest that the use of 5-FU-SUL-PLGA NPs is a promising strategy to enhance 5-FU efficacy against CRC.

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MiR-454-3p Promotes Oxaliplatin Resistance by Targeting PTEN in Colorectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.638537 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiao-Lan Qian ◽

Fang Zhou ◽

Song Xu ◽

Jian Jiang ◽

Zhi-Peng Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Acquired Resistance ◽

Progression Free Survival ◽

Underlying Mechanism ◽

Oxaliplatin Treatment ◽

Colorectal Cancer Cells ◽

Cellular Apoptosis ◽

Hct 116 ◽

Resistant Cells

Colorectal cancer is one of the most common malignancies worldwide. Oxaliplatin is the first-line chemotherapeutic agent for the treatment of advanced colorectal cancer. However, acquired resistance to oxaliplatin limits its therapeutic efficacy, and the underlying mechanism remains largely unclear. In this study, we compared the expression of a panel of microRNAs (miRNAs) between oxaliplatin-sensitive and -resistant HCT-116 colorectal cancer cells. We found that miR-454-3p was significantly up-regulated in oxaliplatin-resistant cells and was the most differently expressed miRNA. Interestingly, we observed that inhibition of miR-454-3p resensitized resistant cells to oxaliplatin and enhanced oxaliplatin-induced cellular apoptosis. Moreover, we determined that miR-454-3p promoted oxaliplatin resistance through targeting PTEN and activating the AKT signaling pathway. In vivo study revealed that overexpression of miR-454-3p decreased the sensitivity of HCT-116 xenograft tumors to oxaliplatin treatment in a mouse model. Clinically, overexpression of miR-454-3p was associated with decreased responsiveness to oxaliplatin-based chemotherapy, as well as a short progression-free survival. Taken together, our study indicated that the expression of miR-454-3p could be used to predict oxaliplatin sensitivity, and targeting miR-454-3p could overcome oxaliplatin resistance in colorectal cancer.

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EPHA2 receptor is involved in in vivo acquired resistance to anti-epidermal growth factor receptor (EGFR) treatment in metastatic colorectal cancer

Annals of Oncology ◽

10.1093/annonc/mdx422.033 ◽

2017 ◽

Vol 28 ◽

pp. vi13

Author(s):

G. Martini ◽

V. Belli ◽

P.P. Vitiello ◽

T. Troiani ◽

C. Cardone ◽

...

Keyword(s):

Colorectal Cancer ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Metastatic Colorectal Cancer ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Epidermal Growth

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Reposition of the anti-inflammatory drug diacerein in an in-vivo colorectal cancer model

Saudi Pharmaceutical Journal ◽

10.1016/j.jsps.2021.12.009 ◽

2021 ◽

Author(s):

Raghda T. Abdel-Latif ◽

Walaa Wadie ◽

Yousra Abdel-mottaleb ◽

Dalaal M. Abdallah ◽

Nabila N. El-Maraghy ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Model ◽

Inflammatory Drug ◽

Anti Inflammatory

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Methods for Evaluating Effects of an Irinotecan + 5-Fluorouracil/Leucovorin (IFL) Regimen in an Orthotopic Metastatic Colorectal Cancer Model Utilizing In Vivo Bioluminescence Imaging

Methods in Molecular Biology - Mouse Models for Drug Discovery ◽

10.1007/978-1-60761-058-8_14 ◽

2009 ◽

pp. 235-252 ◽

Cited By ~ 5

Author(s):

David Surguladze ◽

Philipp Steiner ◽

Marie Prewett ◽

James R. Tonra

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Bioluminescence Imaging ◽

Cancer Model ◽

In Vivo Bioluminescence Imaging

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Role of metalloproteinase-7 in oxaliplatin acquired resistance in colorectal cancer cell lines

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.20042 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 20042-20042 ◽

Cited By ~ 2

Author(s):

V. Almendro ◽

J. Maurel ◽

J. Augé ◽

G. Laus ◽

J. Domingo-Domenech ◽

...

Keyword(s):

Colorectal Cancer ◽

Western Blot ◽

Cell Line ◽

Cell Lines ◽

Acquired Resistance ◽

Resistant Cell ◽

Resistant Cell Line ◽

Fasl Expression ◽

Ic50 Values

20042 Background: Mechanisms responsible for acquired resistance in colorectal cancer (CRC) tumors are not well understood. Anticancer drugs have been shown to enhance FASL expression by NF-kB induction. Additionally Metalloproteinase (MMP)-7 is over-expressed in CRC and has been shown to inhibit apoptosis by cleavage of FASL. We have previously shown in vivo that, sFASL increment was associated with acquired chemoresistance. Therefore we speculate that inhibition of MMP-7 or NF-kB can reverse chemoresistance in CRC cell lines. Methods: We generated an oxaliplatin-resistant cells (HT29R) from a p53 mutated (HT29) cell line. Both cell lines were cultured for 72h with different concentrations of oxaliplatin, BAY11–7085 (inhibitor of NF-kB activation), 0.01 mM of the MMP-7 inhibitor 1,10-Phenanthroline monohydrate (1,10-PM) and 100 ng/ml of DX2 monoclonal antibody. Different drug combinations were performed. Citotoxicity was determined by the MTS method, and cell cycle was analysed at 72h. Cell lines were characterized for MMP-7 expression (ELISA), NF-KB (Western-Blot), Fas expression (immunohistochemistry) and FasL expression (Western-Blot). Results: FAS was down-expressed in HT29R compared to HT29. The HT29R cells showed a IC50 for oxaliplatin 2-fold higher than normal cells. Treatment with 1,10-PM decrease MMP-7 levels (p < 0.005) compared with untreated cells. Additionally, inhibition of MMP-7, restore IC50 values after oxaliplatin treatment in HT29R without changes in NF-KB expression. This oxaliplatin-resistant cell line, presents also sensibility for BAY11–7085, without affecting MMP-7 levels. Finally the addition of oxaliplatin to the MMP-7 inhibitor, increase FAS-mediated apoptosis (induced by DX2 antibody), suggesting that FASL cleavage is responsable of sensitivity. Conclusions: Reversal of oxaliplatin chemo-resistance can be obtained either by MMP-7 or NF-kB inhibition. Both drugs induced sFASL decrement, by inhibiting cleavage or expression, respectively. No significant financial relationships to disclose.

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Role of sphingosine kinase 1 (SphK1) on cetuximab resistance in colorectal cancer models.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13509 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13509-e13509

Author(s):

Roberto Bianco ◽

Roberta Rosa ◽

Lucia Nappi ◽

Luigi Formisano ◽

Vincenzo Damiano ◽

...

Keyword(s):

Colorectal Cancer ◽

Anticancer Agents ◽

Acquired Resistance ◽

Sphingosine Kinase ◽

Sphingosine Kinase 1 ◽

Mutational Status ◽

Resistant Cells

e13509 Background: Although EGFR inhibitors, such as the mAb cetuximab, represent an effective strategy in colorectal cancer (CRC), the clinical use of these agents is limited by intrinsic or acquired resistance. Alterations in the ‘sphingolipid rheostat’, or the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P), due to overactivation of sphingosine kinase 1 (SphK1), have been involved in the regulation of resistance to anticancer agents. Since some studies described cross-talks between SphK1 and EGFR-dependent signalling pathways, we investigated the contribution of SphK1 to cetuximab resistance in CRC models. Methods: We used CRC cell lines with both intrinsic or acquired resistance to cetuximab. In these models, we analyzed SphK1 expression/activation by using different tools, including the available drug fingolimod (FTY720), both in vitro and in vivo. We confirmed our data through a tissue microarray (TMA)-based analysis on CRC tissues. Results: SphK1 is overexpressed in CRC cells resistant to cetuximab. Higher doses of N,N-dimethylsphingosine (DMS), a potent competitive inhibitor of SphK1, are needed to achieve complete enzyme saturation and survival inhibition in resistant cells. Moreover, ceramide induces apoptosis less efficiently in resistant than in sensitive cells, consistently with the idea that increased SphK1 levels mediate S1P synthesis by ceramide in resistant cells. SphK1 contribution to resistance is supported by the demonstration that SphK1 inhibition by DMS or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in wild-type cells confers resistance. Re-sensitization to cetuximab is observed after treatment with fingolimod, a S1P receptor inhibitor, both in vitro and in nude mice xenografted with CRC cells. Finally, a TMA-based analysis on CRC tissues revealed that SphK1 expression is related to K-Ras mutational status, a well-known determinant of cetuximab resistance. Conclusions: Our data could clarify the role of SphK1 in the onset of resistance to cetuximab, thus suggesting SphK1 inhibition as a part of novel targeting strategies for resistant cancer patients.

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Polydopamine-Based “Four-in-One” Versatile Nanoplatforms for Targeted Dual Chemo and Photothermal Synergistic Cancer Therapy

Pharmaceutics ◽

10.3390/pharmaceutics11100507 ◽

2019 ◽

Vol 11 (10) ◽

pp. 507 ◽

Cited By ~ 11

Author(s):

Liu ◽

Gao ◽

Zhou ◽

Nie ◽

Cheng ◽

...

Keyword(s):

Cancer Therapy ◽

Anticancer Drug ◽

Near Infrared ◽

Polymeric Nanoparticles ◽

Carcinoma Cells ◽

Promising Strategy ◽

Human Breast Carcinoma Cells ◽

Mcf 7

Abstract: The development of versatile nanoscale drug delivery systems that integrate with multiple therapeutic agents or methods and improve the efficacy of cancer therapy is urgently required. To satisfy this demand, polydopamine (PDA)-modified polymeric nanoplatforms were constructed for the dual loading of chemotherapeutic drugs. The hydrophobic anticancer drug docetaxel (DTX) was loaded into the polymeric nanoparticles (NPs) which were fabricated from the star-shaped copolymer CA-PLGA. Then DTX-loaded NPs were coated with PDA, followed by conjugation of polyelethyl glycol (PEG)-modified targeting ligand aptamer AS1411(Apt) and adsorption of the hydrophilic anticancer drug doxorubicin (DOX). This “four-in-one” nanoplatform, referred to as DTX/NPs@PDA/DOX-PEG-Apt, demonstrated high near-infrared photothermal conversion efficiency and exhibited pH and thermo-responsive drug release behavior. Furthermore, it was able to specifically target MCF-7 human breast carcinoma cells and provide synergistic chemo-photothermal therapy to further improve the anticancer effect both in vitro and in vivo, providing a novel promising strategy for cancer therapy.

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Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1497-0 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 3

Author(s):

S. Napolitano ◽

N. Matrone ◽

A. L. Muddassir ◽

G. Martini ◽

A. Sorokin ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

Combined Treatment ◽

Acquired Resistance ◽

Mek Inhibitor ◽

Gene Signature ◽

Mapk Signaling

Abstract Background Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. Methods We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. Results The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. Conclusions These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.

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