Systemic Therapy of Cholangiocarcinoma

Plentz, Ruben R.; Malek, Nisar P.

doi:10.1159/000453084

Cited by 27 publications

(13 citation statements)

References 57 publications

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“…Surgical resection and liver transplantation are the only effective treatment options for early-stage disease, but most CCA patients are diagnosed at advanced stages 1 . For unresectable CCA, combined administration of Gemcitabine and Platin-based drugs is the standard first line chemotherapy 4,5 . However, the response to such treatment is limited and it confers a median overall survival of only 11.7 months 1,6 .…”

Section: Introductionmentioning

confidence: 99%

MEK inhibition suppresses K-Ras wild-type cholangiocarcinoma in vitro and in vivo via inhibiting cell proliferation and modulating tumor microenvironment

et al. 2019

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PD901, a MEK inhibitor, has been demonstrated of therapeutic efficacy against cholangiocarcinoma (CCA) harboring K-Ras oncogenic mutations. However, most CCA exhibit no K-Ras mutations. In the current study, we investigated the therapeutic potential of PD901, either alone or in combination with the pan-mTOR inhibitor MLN0128, for the treatment of K-Ras wild-type CCA in vitro using human CCA cell lines, and in vivo using AKT/YapS127A CCA mouse model. We discovered that in vitro, PD901 treatment strongly inhibited CCA cell proliferation, and combined PD901 and MLN0128 therapy further increased growth inhibition. In vivo, treatment of PD901 alone triggered tumor regression, which was not further increased when the two drugs were administered simultaneously. Mechanistically, PD901 efficiently hampered ERK activation in vitro and in vivo, leading to strong inhibition of CCA tumor cell cycle progression. Intriguingly, we discovered that PD901, but not MLN0128 treatment resulted in changes affecting the vasculature and cancer-associated fibroblasts in AKT/YapS127A mouse lesions. It led to the decreased hypoxia within tumor lesions, which may further enhance the anti-cell proliferation activities of PD901. Altogether, our study demonstrates that MEK inhibitors could be effective for the treatment of K-Ras wild-type CCA via inhibiting cell proliferation and modulating tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

MEK inhibition suppresses K-Ras wild-type cholangiocarcinoma in vitro and in vivo via inhibiting cell proliferation and modulating tumor microenvironment

et al. 2019

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“…It is used for treatment of cholangiocarcinoma and other types of biliary cancer. The general side effects include bone marrow suppression, liver and kidney problems, nausea, fever, rash, shortness of breath and hair loss [31][32][33][34]. Therefore, for today, the possibility is actively studied to use GC in composition of magnetically sensitive NC and ML on their basis to create multi-functional antitumor medicines for targeted delivery and local therapy [35][36][37][38].…”

Section: Experimental Part and Discussionmentioning

confidence: 99%

Magnetically sensitive nanocomposites and magnetic liquids based on magnetite, gemcitabine, and antibody HER2

Petranovska¹,

Абрамов²,

Опанащук³

et al. 2019

Him. Fiz. Tehnol. Poverhni

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The processes of adsorption of gemcitabine (GC) on the surface of nanosized singledomain magnetite (Fe 3 O 4) have been investigated. Under the experiment conditions, the value of adsorption capacity A was ~ 37.2 mg/g, the extraction extent U = 33.13 %, the separation factor E = 82.58 mL/g. It has been determined that adsorption corresponds to the Freundlich model. The magnetic properties of nanocomposites (NС) Fe 3 O 4 @GC have been investigated. The average value of the thickness of the adsorbed layer of GC in the composition of Fe 3 O 4 @GC NC is 2.4±0.1 nm, as evaluated by the method of magnetic granulometry. Magnetic liquids (ML) have been synthesized based on magnetite and physiological solution (PS) stabilized with sodium oleate (Ol.Na) and polyethylene glycol (PEG), which contain GC and antibody (AB) HER2 (Fe 3 O 4 @GC/Ol.Na/PEG+PS). The properties of ML were investigated as well as cytotoxic/cytostatic activity with respect to HepG2 hepatocellular carcinoma of human liver. Parameters of ML based on magnetite were found: Fe 3 O 4 concentration-14 mg/mL, Fe 3 O 4 particle size-4-22 nm, average size of Fe 3 O 4 particles-10.8 nm; the average size of Fe 3 O 4 particles stabilized with sodium oleate-16.8 nm, saturation magnetization M ∞ = 14.1±2.5 % Gs, hypsometric height-25±10 % cm, viscosity η = 1.14±3 % mPa•s, density ρ ML = 1.14 ± 1.0 % g/cm 3 , the concentration of GC was 1.25 mg/mL, that of HER2 AB was 3.75 μg/mL. We have obtained the calculated and graphic data concerning the dependence of the surface area and the specific magnetization of saturation of Fe 3 O 4 @GC/Ol.Na/PEG on the thickness of GC layer, which can be useful for predicting of the nanoscale architecture of magnetically sensitive NC and ML in the manufacture of relative drugs. The synergistic nature of the influence of GC/Fe 3 O 4 /HER2 complex on HepG2 cells was revealed. It has been determined that IC50 for ML is 0.155 mg/mL, in the range of concentration of 0.025-0.1 mg/mL, ML is biocompatible with HepG2 cells. It has been shown that HER2 AB used alone in the investigated concentrations does not affect HepG2 cell viability/proliferation. In vitro, GC inhibits the proliferation of liver carcinoma cells, the IC50 value has been 0.002 mg/mL. The use of ML in complex with GC can increase the cytotoxic activity of the composite by 8-10 %. The ML+GC+HER2 AB complexes caused the synergistic effect and an increase in the cytotoxic activity, compared with GC used alone, up to 18-20 %, while GC contents reduced to 0.008 mg/mL. The results of the studies indicate that the use of ML based on magnetite, gemcitabine, and antibody increases the effectiveness of the antitumor medicines with a significant reduction in their dose and, respectively, the toxicoallergic reactions of the body, and nanosized magnetite can be promising for the manufacture of magnetically sensitive adsorption materials for medical purposes, e.g. for detoxification of an organism after GC therapy.

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“…Common side effects include bone marrow suppression, liver and kidney problems, nausea, fever, rash, shortness of breath, and hair loss. GC belongs to the list of the basic medicines of the World Health Organization, the most effective and safe medicines needed in a health system, it is commonly used off-label to treat cholangiocarcinoma and other biliary tract cancers [23,24].…”

Section: Experimental Techniquesmentioning

confidence: 99%

Synthesis and properties of magnetically sensitive nanocomposites based on magnetite and gemcitabine

Petranovska¹,

Абрамов²,

Опанащук³

et al. 2018

Him. Fiz. Tehnol. Poverhni

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The aim of the work is synthesis of new polyfunctional magnetosensitive nanocomposites (NC) capable of the targeted delivery in the tumors of hepatocellular carcinoma and intrahepatic cholangiocarcinoma of a drug with chemotherapeutic mechanism of action-gemcitabine (GC), and deposition with the help of magnetic field, investigation of the basic physico-chemical properties of NC. Research direction includes synthesis of nanosized one-domain magnetite as a magnetically sensitive carrier, modification of its surface by carbon covering with the aim of stabilization and chemical functionalization, biofunctionalization of NC by GC immobilization.

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Systemic Therapy of Cholangiocarcinoma

Cited by 27 publications

References 57 publications

MEK inhibition suppresses K-Ras wild-type cholangiocarcinoma in vitro and in vivo via inhibiting cell proliferation and modulating tumor microenvironment

MEK inhibition suppresses K-Ras wild-type cholangiocarcinoma in vitro and in vivo via inhibiting cell proliferation and modulating tumor microenvironment

Magnetically sensitive nanocomposites and magnetic liquids based on magnetite, gemcitabine, and antibody HER2

Synthesis and properties of magnetically sensitive nanocomposites based on magnetite and gemcitabine

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