scholarly journals Human Tumor–Derived Matrix Improves the Predictability of Head and Neck Cancer Drug Testing

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 92 ◽  
Author(s):  
Katja Tuomainen ◽  
Ahmed Al-Samadi ◽  
Swapnil Potdar ◽  
Laura Turunen ◽  
Minna Turunen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Head And Neck ◽  
Cancer Cells ◽  
Drug Testing ◽  
Human Tumor ◽  
Response Rates ◽  
Cancer Drug ◽  
Anticancer Compounds ◽  
Culturing Conditions

In vitro cancer drug testing carries a low predictive value. We developed the human leiomyoma–derived matrix “Myogel” to better mimic the human tumor microenvironment (TME). We hypothesized that Myogel could provide an appropriate microenvironment for cancer cells, thereby allowing more in vivo–relevant drug testing. We screened 19 anticancer compounds, targeting the epidermal growth factor receptor (EGFR), MEK, and PI3K/mTOR on 12 head and neck squamous cell carcinoma (HNSCC) cell lines cultured on plastic, mouse sarcoma–derived Matrigel (MSDM), and Myogel. We applied a high-throughput drug screening assay under five different culturing conditions: cells in two-dimensional (2D) plastic wells and on top or embedded in Matrigel or Myogel. We then compared the efficacy of the anticancer compounds to the response rates of 19 HNSCC monotherapy clinical trials. Cancer cells on top of Myogel responded less to EGFR and MEK inhibitors compared to cells cultured on plastic or Matrigel. However, we found a similar response to the PI3K/mTOR inhibitors under all culturing conditions. Cells grown on Myogel more closely resembled the response rates reported in EGFR-inhibitor monotherapy clinical trials. Our findings suggest that a human tumor matrix improves the predictability of in vitro anticancer drug testing compared to current 2D and MSDM methods.

‘In vitro clinical trials’ platform for drug testing in patient-derived ex vivo 3D cultured human tumor tissues

2020 ◽  
Vol 138 ◽  
pp. S59
Author(s):  
N. Beztsinna ◽  
F. Grillet ◽  
A. Jariani ◽  
J. Overkamp ◽  
D. van der Meer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Testing ◽  
Ex Vivo ◽  
Human Tumor ◽  
Tumor Tissues

scholarly journals Radiosensitising Cancer Using Phosphatidylinositol-3-Kinase (PI3K), Protein Kinase B (AKT) or Mammalian Target of Rapamycin (mTOR) Inhibitors

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1278 ◽  
Author(s):  
Kasun Wanigasooriya ◽  
Robert Tyler ◽  
Joao D. Barros-Silva ◽  
Yashashwi Sinha ◽  
Tariq Ismail ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Head And Neck ◽  
Cancer Cells ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Current Evidence ◽  
Mtor Inhibition ◽  
Ample Evidence

Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.

Influence of New Synthetic Xanthones on the Proliferation and Migration Potential of Cancer Cell Lines In Vitro

2020 ◽  
Vol 19 (16) ◽  
pp. 1949-1965 ◽  
Author(s):  
Natalia Szkaradek ◽  
Daniel Sypniewski ◽  
Dorota Żelaszczyk ◽  
Sabina Gałka ◽  
Paulina Borzdziłowska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Higher Plants ◽  
Biological Activities ◽  
Human Tumor ◽  
Plant Metabolites ◽  
Xtt Assay ◽  
Treatment Protocols

Background: Natural plant metabolites and their semisynthetic derivatives have been used for years in cancer therapy. Xanthones are oxygenated heterocyclic compounds produced as secondary metabolites by higher plants, fungi or lichens. Xanthone core may serve as a template in the synthesis of many derivatives that have broad biological activities. Objective: This study synthesized a series of 17 new xanthones, and their anticancer potential was also evaluated. Methods: The anticancer potential was evaluated in vitro using a highly invasive T24 cancer cell line. Direct cytotoxic effects of the xanthones were established by IC50 estimation based on XTT assay. Results: 5 compounds of the total 17 showed significant cytotoxicity toward the studied cancer cultures and were submitted to further detailed analysis, including studies examining their influence on gelatinase A and B expression, as well as on the cancer cells migration and adhesion to an extracellular matrix. These analyses were carried out on five human tumor cell lines: A2780 (ovarian cancer), A549 (lung cancer), HeLa (cervical cancer), Hep G2 (liver cancer), and T24 (urinary bladder cancer). All the compounds, especially 4, showed promising anticancer activity: they exhibited significant cytotoxicity towards all the evaluated cell lines, including MCF-7 breast cancer, and hindered migration-motility activity of cancer cells demonstrating more potent activity than α-mangostin which served as a reference xanthone. Conclusion: These results suggest that our xanthone derivatives may be further analyzed in order to include them in cancer treatment protocols.

Polymer Coated Iron Nanoparticles: Radiolabeling & In Vitro Studies

2020 ◽  
Vol 13 ◽  
Author(s):  
Selin Yılmaz ◽  
Çiğdem İçhedef ◽  
Kadriye Buşra Karatay ◽  
Serap Teksöz
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Iron Oxide ◽  
Cancer Cells ◽  
Iron Oxide Nanoparticles ◽  
Breast Cancer Cells ◽  
Cancer Drug ◽  
Oxide Nanoparticles ◽  
Sem Images

Backgorund: Superparamagnetic iron oxide nanoparticles (SPIONs) have been extensively used for targeted drug delivery systems due to their unique magnetic properties. Objective: In this study, it’s aimed to develop a novel targeted 99mTc radiolabeled polymeric drug delivery system for Gemcitabine (GEM). Methods: Gemcitabine, an anticancer agent, was encapsulated into polymer nanoparticles (PLGA) together with iron oxide nanoparticles via double emulsion technique and then labeled with 99mTc. SPIONs were synthesized by reduction–coprecipitation method and encapsulated with oleic acid for surface modification. Size distribution and the morphology of the synthesized nanoparticles were caharacterized by dynamic light scattering(DLS)and scanning electron microscopy(SEM), respectively. Radiolabeling yield of SPION-PLGAGEM nanoparticles were determined via Thin Layer Radio Chromatography (TLRC). Cytotoxicity of GEM loaded SPION-PLGA were investigated on MDA-MB-231 and MCF7 breast cancer cells in vitro. Results: SEM images displayed that the average size of the drug-free nanoparticles was 40 nm and the size of the drug-loaded nanoparticles was 50 nm. The diameter of nanoparticles were determined as 366.6 nm by DLS, while zeta potential was found as-29 mV. SPION was successfully coated with PLGA, which was confirmed by FTIR. GEM encapsulation efficiency of SPION-PLGA was calculated as 4±0.16 % by means of HPLC. Radiolabeling yield of SPION-PLGA-GEM nanoparticles were determined as 97.8±1.75 % via TLRC. Cytotoxicity of GEM loaded SPION-PLGA were investigated on MDA-MB-231 and MCF7 breast cancer cells. SPION-PLGA-GEM showed high uptake on MCF-7, whilst incorporation rate was increased for both cell lines which external magnetic field application. Conclusion: 99mTc labeled SPION-PLGA nanoparticles loaded with GEM may overcome some of the obstacles in anti-cancer drug delivery because of their appropriate size, non-toxic, and supermagnetic characteristics.

scholarly journals A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

2021 ◽  
Vol 22 (16) ◽  
pp. 8372
Author(s):  
Ana María Zárate ◽  
Christian Espinosa-Bustos ◽  
Simón Guerrero ◽  
Angélica Fierro ◽  
Felipe Oyarzún-Ampuero ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Antitumour Activity ◽  
Anticancer Compounds ◽  
Human Cancer Cells ◽  
Cycle Arrest ◽  
Apoptosis Inducer ◽  
Purine Ring

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.

Prevascularized, Co-Culture Model for Breast Cancer Drug Development

2012 ◽  
Author(s):  
Lauren Marshall ◽  
Isabel Löwstedt ◽  
Paul Gatenholm ◽  
Joel Berry
Keyword(s):  
Breast Cancer ◽  
Drug Development ◽  
Three Dimensional ◽  
Human Tumor ◽  
3D Models ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Anti Cancer

The objective of this study was to create 3D engineered tissue models to accelerate identification of safe and efficacious breast cancer drug therapies. It is expected that this platform will dramatically reduce the time and costs associated with development and regulatory approval of anti-cancer therapies, currently a multi-billion dollar endeavor [1]. Existing two-dimensional (2D) in vitro and in vivo animal studies required for identification of effective cancer therapies account for much of the high costs of anti-cancer medications and health insurance premiums borne by patients, many of whom cannot afford it. An emerging paradigm in pharmaceutical drug development is the use of three-dimensional (3D) cell/biomaterial models that will accurately screen novel therapeutic compounds, repurpose existing compounds and terminate ineffective ones. In particular, identification of effective chemotherapies for breast cancer are anticipated to occur more quickly in 3D in vitro models than 2D in vitro environments and in vivo animal models, neither of which accurately mimic natural human tumor environments [2]. Moreover, these 3D models can be multi-cellular and designed with extracellular matrix (ECM) function and mechanical properties similar to that of natural in vivo cancer environments [3].

scholarly journals Ionizing radiation affects the composition of the proteome of extracellular vesicles released by head-and-neck cancer cells in vitro

2019 ◽  
Vol 60 (3) ◽  
pp. 289-297 ◽  
Author(s):  
Agata Abramowicz ◽  
Anna Wojakowska ◽  
Lukasz Marczak ◽  
Malgorzata Lysek-Gladysinska ◽  
Mateusz Smolarz ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Ionizing Radiation ◽  
Head And Neck ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Neck Cancer

scholarly journals Implementation of the NCI-60 Human Tumor Cell Line Panel to Screen 2260 Cancer Drug Combinations to Generate >3 Million Data Points Used to Populate a Large Matrix of Anti-Neoplastic Agent Combinations (ALMANAC) Database

2018 ◽  
Vol 24 (3) ◽  
pp. 242-263 ◽  
Author(s):  
David A. Close ◽  
Allen Xinwei Wang ◽  
Stanton J. Kochanek ◽  
Tongying Shun ◽  
Julie L. Eiseman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Growth Inhibition ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Cancer Drug ◽  
Large Matrix ◽  
Data Points

Animal and clinical studies demonstrate that cancer drug combinations (DCs) are more effective than single agents. However, it is difficult to predict which DCs will be more efficacious than individual drugs. Systematic DC high-throughput screening (HTS) of 100 approved drugs in the National Cancer Institute’s panel of 60 cancer cell lines (NCI-60) produced data to help select DCs for further consideration. We miniaturized growth inhibition assays into 384-well format, increased the fetal bovine serum amount to 10%, lengthened compound exposure to 72 h, and used a homogeneous detection reagent. We determined the growth inhibition 50% values of individual drugs across 60 cell lines, selected drug concentrations for 4 × 4 DC matrices (DCMs), created DCM master and replica daughter plate sets, implemented the HTS, quality control reviewed the data, and analyzed the results. A total of 2620 DCMs were screened in 60 cancer cell lines to generate 3.04 million data points for the NCI ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations) database. We confirmed in vitro a synergistic drug interaction flagged in the DC HTS between the vinca-alkaloid microtubule assembly inhibitor vinorelbine (Navelbine) tartrate and the epidermal growth factor-receptor tyrosine kinase inhibitor gefitinib (Iressa) in the SK-MEL-5 melanoma cell line. Seventy-five percent of the DCs examined in the screen are not currently in the clinical trials database. Selected synergistic drug interactions flagged in the DC HTS described herein were subsequently confirmed by the NCI in vitro, evaluated mechanistically, and were shown to have greater than single-agent efficacy in mouse xenograft human cancer models. Enrollment is open for two clinical trials for DCs that were identified in the DC HTS. The NCI ALMANAC database therefore constitutes a valuable resource for selecting promising DCs for confirmation, mechanistic studies, and clinical translation.

scholarly journals Targeting UCP2 Suppresses the FAK Signaling and Progression of Human Head and Neck Cancer Cells

2020 ◽  
pp. 1-8
Author(s):  
Yunfeng Zhao ◽  
Cherie Ann Nathan ◽  
Chunjing Zhang ◽  
Hongyan Du ◽  
Manikandan Panchatcharam ◽  
...  
Keyword(s):  
Head And Neck ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Uncoupling Protein ◽  
Human Head ◽  
Atp Production ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Lactate Formation

Background: New adjuvant therapies for human head and neck (H&N) cancer to improve the quality of life of the patients are in great demand. Our early studies have demonstrated that uncoupling protein 2 (UCP2) is upregulated in the tumor tissues of H&N cancer compared to the adjacent normal tissues; however, the role of UCP2 in H&N cancer has not been studied. Objective: In this manuscript, we aim to examine whether UCP2 contributes to H&N cancer progression in vitro. Methods: We generated UCP2 stable knockdown H&N cancer cells and detected the effects of UCP2 inhibition on cell proliferation, migration, invasion, 3D spheroid formation, and the sensitivity to a chemodrug treatment. Results: Knockdown of UCP2 suppressed the progression of H&N cancer in vitro, which might be mediated via the following mechanism: 1) increased the G1 phase whereas decreased the S phase of the cell cycle, which could be mediated by suppression of the G1/S regulators including CDK4/6 and cyclin D1. 2) Decreased mitochondrial oxygen consumption, ATP production, and lactate formation, which is consistent with the downregulation of c-Myc. 3) FAK may serve as the upstream signaling molecule, and its action was mediated by Akt and ERK. Conclusions: Our studies first demonstrate that targeting UCP2 may suppress H&N cancer progression in vitro.

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