3D Bioprinted Vascularized Tumour for Drug Testing

An in vitro screening system for anti-cancer drugs cannot exactly reflect the efficacy of drugs in vivo, without mimicking the tumour microenvironment (TME), which comprises cancer cells interacting with blood vessels and fibroblasts. Additionally, the tumour size should be controlled to obtain reliable and quantitative drug responses. Herein, we report a bioprinting method for recapitulating the TME with a controllable spheroid size. The TME was constructed by printing a blood vessel layer consisting of fibroblasts and endothelial cells in gelatine, alginate, and fibrinogen, followed by seeding multicellular tumour spheroids (MCTSs) of glioblastoma cells (U87 MG) onto the blood vessel layer. Under MCTSs, sprouts of blood vessels were generated and surrounding MCTSs thereby increasing the spheroid size. The combined treatment involving the anti-cancer drug temozolomide (TMZ) and the angiogenic inhibitor sunitinib was more effective than TMZ alone for MCTSs surrounded by blood vessels, which indicates the feasibility of the TME for in vitro testing of drug efficacy. These results suggest that the bioprinted vascularized tumour is highly useful for understanding tumour biology, as well as for in vitro drug testing.

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Treatment with Uncaria tomentosa Promotes Apoptosis in B16-BL6 Mouse Melanoma Cells and Inhibits the Growth of B16-BL6 Tumours

Molecules ◽

10.3390/molecules26041066 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1066

Author(s):

Ali Zari ◽

Hajer Alfarteesh ◽

Carly Buckner ◽

Robert Lafrenie

Keyword(s):

Tumour Size ◽

Melanoma Cells ◽

Tunel Staining ◽

Aqueous Extracts ◽

Ki 67 ◽

Uncaria Tomentosa ◽

Mouse Melanoma ◽

Anti Cancer

Uncaria tomentosa is a medicinal plant native to Peru that has been traditionally used in the treatment of various inflammatory disorders. In this study, the effectiveness of U. tomentosa as an anti-cancer agent was assessed using the growth and survival of B16-BL6 mouse melanoma cells. B16-BL6 cell cultures treated with both ethanol and phosphate-buffered saline (PBS) extracts of U. tomentosa displayed up to 80% lower levels of growth and increased apoptosis compared to vehicle controls. Treatment with ethanolic extracts of Uncaria tomentosa were much more effective than treatment with aqueous extracts. U. tomentosa was also shown to inhibit B16-BL6 cell growth in C57/bl mice in vivo. Mice injected with both the ethanolic and aqueous extracts of U. tomentosa showed a 59 ± 13% decrease in B16-BL6 tumour weight and a 40 ± 9% decrease in tumour size. Histochemical analysis of the B16-BL6 tumours showed a strong reduction in the Ki-67 cell proliferation marker in U. tomentosa-treated mice and a small, but insignificant increase in terminal transferase dUTP nick labelling (TUNEL) staining. Furthermore, U. tomentosa extracts reduced angiogenic markers and reduced the infiltration of T cells into the tumours. Collectively, the results in this study concluded that U. tomentosa has potent anti-cancer activity that significantly inhibited cancer cells in vitro and in vivo.

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Prevascularized, Co-Culture Model for Breast Cancer Drug Development

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80409 ◽

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].

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Frontiers in Anti-cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-angiogenic Add-on Therapy in Glioblastoma

10.20944/preprints202111.0531.v1 ◽

2021 ◽

Author(s):

Laura Guarnaccia ◽

Stefania Elena Navone ◽

Matteo Maria Masseroli ◽

Melissa Balsamo ◽

Manuela Caroli ◽

...

Keyword(s):

Target Therapy ◽

Cancer Drug ◽

Cancer Drug Discovery ◽

Average Survival ◽

Anti Cancer ◽

Tumor Neovascularization ◽

Novel Therapeutic Strategies

Glioblastoma (GBM) is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. GBM shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including GBM. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of the inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss the potential metformin’s antitumoral effects on GBM, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of GBM patients.

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Coherent Raman Scattering Microscopy in Oncology Pharmacokinetic Research

Frontiers in Pharmacology ◽

10.3389/fphar.2021.630167 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junjie Zeng ◽

Wenying Zhao ◽

Shuhua Yue

Keyword(s):

Raman Scattering ◽

High Speed ◽

Cancer Drug ◽

Cancer Drugs ◽

High Speed Imaging ◽

Coherent Raman Scattering ◽

Anti Cancer ◽

Coherent Raman

The high attrition rates of anti-cancer drugs during clinical development remains a bottleneck problem in pharmaceutical industry. This is partially due to the lack of quantitative, selective, and rapid readouts of anti-cancer drug activity in situ with high resolution. Although fluorescence microscopy has been commonly used in oncology pharmacological research, fluorescent labels are often too large in size for small drug molecules, and thus may disturb the function or metabolism of these molecules. Such challenge can be overcome by coherent Raman scattering microscopy, which is capable of chemically selective, highly sensitive, high spatial resolution, and high-speed imaging, without the need of any labeling. Coherent Raman scattering microscopy has tremendously improved the understanding of pharmaceutical materials in the solid state, pharmacokinetics of anti-cancer drugs and nanocarriers in vitro and in vivo. This review focuses on the latest applications of coherent Raman scattering microscopy as a new emerging platform to facilitate oncology pharmacokinetic research.

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New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function

Cancers ◽

10.3390/cancers12061523 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1523 ◽

Cited By ~ 1

Author(s):

Yuanyuan Fu ◽

Qianqian Gu ◽

Li Luo ◽

Jiecheng Xu ◽

Yuping Luo ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Therapy ◽

Therapeutic Strategy ◽

Screening Method ◽

Cancer Drug ◽

Autophagic Flux ◽

Single Target ◽

Anti Cancer

Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy.

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Validation of a novel perfusion bioreactor system in cancer research

Hemijska industrija ◽

10.2298/hemind200329015s ◽

2020 ◽

Vol 74 (3) ◽

pp. 187-196

Author(s):

Jasmina Stojkovska ◽

Jovana Zvicer ◽

Milena Milivojevic ◽

Isidora Petrovic ◽

Milena Stevanovic ◽

...

Keyword(s):

Cancer Research ◽

Drug Screening ◽

Cancer Drug ◽

Perfusion Bioreactor ◽

Animal Testing ◽

Anti Cancer ◽

Medium Flow ◽

Bioreactor System

Development of drugs is a complex, time- and cost-consuming process due to the lack of standardized and reliable characterization techniques and models. Traditionally, drug screening is based on in vitro analysis using two-dimensional (2D) cell cultures followed by in vivo animal testing. Unfortunately, application of the obtained results to humans in about 90 % of cases fails. Therefore, it is important to develop and improve cell-based systems that can mimic the in vivo-like conditions to provide more reliable results. In this paper, we present development and validation of a novel, user-friendly perfusion bioreactor system for single use aimed for cancer research, drug screening, anti-cancer drug response studies, biomaterial characterization, and tissue engineering. Simple design of the perfusion bioreactor provides direct medium flow at physiological velocities (100?250 ?m s-1) through samples of different sizes and shapes. Biocompatibility of the bioreactor was confirmed in short term cultivation studies of cervical carcinoma SiHa cells immobilized in alginate microfibers under continuous medium flow. The results have shown preserved cell viability indicating that the perfusion bioreactor in conjunction with alginate hydrogels as cell carriers could be potentially used as a tool for controlled anti-cancer drug screening in a 3D environment.

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Reversine: A Synthetic Purine with a Dual Activity as a Cell Dedifferentiating Agent and a Selective Anticancer Drug

Current Medicinal Chemistry ◽

10.2174/0929867326666190103120725 ◽

2020 ◽

Vol 27 (21) ◽

pp. 3448-3462

Author(s):

Marco Piccoli ◽

Andrea Ghiroldi ◽

Michelle M. Monasky ◽

Federica Cirillo ◽

Giuseppe Ciconte ◽

...

Keyword(s):

Stem Cells ◽

Current Knowledge ◽

Embryonic Stem ◽

Cell Types ◽

Cancer Drug ◽

Anti Cancer ◽

Adult Cell ◽

Induced Pluripotent

The development of new therapeutic applications for adult and embryonic stem cells has dominated regenerative medicine and tissue engineering for several decades. However, since 2006, induced Pluripotent Stem Cells (iPSCs) have taken center stage in the field, as they promised to overcome several limitations of the other stem cell types. Nonetheless, other promising approaches for adult cell reprogramming have been attempted over the years, even before the generation of iPSCs. In particular, two years before the discovery of iPSCs, the possibility of synthesizing libraries of large organic compounds, as well as the development of high-throughput screenings to quickly test their biological activity, enabled the identification of a 2,6-disubstituted purine, named reversine, which was shown to be able to reprogram adult cells to a progenitor-like state. Since its discovery, the effect of reversine has been confirmed on different cell types, and several studies on its mechanism of action have revealed its central role in inhibitory activity on several kinases implicated in cell cycle regulation and cytokinesis. These key features, together with its chemical nature, suggested a possible use of the molecule as an anti-cancer drug. Remarkably, reversine exhibited potent cytotoxic activity against several tumor cell lines in vitro and a significant effect in decreasing tumor progression and metastatization in vivo. Thus, 15 years since its discovery, this review aims at critically summarizing the current knowledge to clarify the dual role of reversine as a dedifferentiating agent and anti-cancer drug.

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KLF5 Inhibition Overcomes Oxaliplatin Resistance In Patient-Derived Colorectal Cancer Organoids by Restoring Apoptotic Response

10.21203/rs.3.rs-130881/v1 ◽

2020 ◽

Author(s):

Xiaohui Shen ◽

Han Gao ◽

Yuchen Zhang ◽

Zhuoqing Xu ◽

Wenqing Feng ◽

...

Keyword(s):

Colorectal Cancer ◽

Chromatin Immunoprecipitation ◽

Combined Treatment ◽

Luciferase Reporter ◽

Cancer Drug ◽

Apoptotic Response ◽

Cancer Drug Resistance ◽

Xenograft Models

Abstract Background: Oxaliplatin resistance is a major challenge for treatment of metastatic colorectal cancer (mCRC). Many molecular targeted drugs for refractory CRC have been developed to solve colorectal cancer drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin- resistance still not clear.Methods: PDOs derived from CRC patients were constructed to conduct the sensitivity assays of oxaliplatin in vitro. Oxaliplatin resistant PDOs were selected and treated under the combined treatment of ML264(a KLF5 inhibitor) and oxaliplatin to determine the effects of KLF5 inhibition on apoptosis. Using CRC cell lines to investigate downstream mechanisms and xenograft models to confirm whether ML264 can restore oxaliplatin sensitivity of CRC cells in vivo.Results: We successfully constructed CRC PDOs and conducted the sensitivity test of oxaliplatin in PDOs from different patients. We found that ML264 restores oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signal pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcomed oxaliplatin resistance in xenograft tumors.Conclusions: Our study demonstrated that ML264 can restores oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 might be a potential therapeutic target for CRC resistant to oxaliplatin. PDOs have strong potential in evaluating inhibitors and drug combinations therapy in a preclinical environment.

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Simultaneous Drug and Gene Delivery from the Biodegradable Poly(ε-caprolactone) Nanofibers for the Treatment of Liver Cancer

Journal of Nanoscience and Nanotechnology ◽

10.1166/jnn.2015.11233 ◽

2015 ◽

Vol 15 (10) ◽

pp. 7971-7975 ◽

Cited By ~ 21

Author(s):

Hui-Lian Che ◽

Hwa Jeong Lee ◽

Koichiro Uto ◽

Mitsuhiro Ebara ◽

Won Jong Kim ◽

...

Keyword(s):

Gene Delivery ◽

Liver Cancer ◽

Sustained Release ◽

Liver Tumors ◽

Cancer Drug ◽

Therapeutic Gene ◽

Anti Cancer ◽

Drug And Gene Delivery

In this study, we present anti-cancer drug containing nanofiber-mediated gene delivery to treat liver cancer. Electro-spun nanofibers have big potential for local delivery and sustained release of therapeutic gene and drugs. We reported a temperature-responsive nanofibers mainly compounded by branched poly(ε-caprolactone) (PCL) macro-monomers and anti-cancer drug paclitaxel. The nanofiber could be administrated into liver tumors to dramatically hinder their growth and prevent their metastasis. As a result, paclitaxel encapsulated PCL (PTX/PCL) nanofibers with diameters of around several tens nanometers to 10 nm were successfully obtained by electro-spinning andobserved in scanning electron microscopy (SEM). Nanoparticles composed of disulfide cross-linked branched PEI (ssPEI) and anti-cancer therapeutic gene miRNA-145 were complexed based on the electrostatic interaction and coated over the paclitaxel-loaded nanofiber. MicroRNA 145/ssPEI nanoparticles (MSNs) immobilized on the PTX/PCL nanofiber showed time-dependent sustained release of the microRNA for enhanced uptake in neighboring liver cancer cells without any noticeable cytotoxicity. From this study we are expecting a synergistic effect on the cancer cell suppression since we have combined the drug and gene delivery. This approach uses the nanofibers and nanoparticles together for the treatment of cancer and the detailed investigation in vitro and in vivo must be conducted for the practicality of this study. The polymer is biodegradable and the toxicity issues must be cleared by our approach.

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Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

Pharmaceuticals ◽

10.3390/ph14050470 ◽

2021 ◽

Vol 14 (5) ◽

pp. 470

Author(s):

Nirmala Tilija Pun ◽

Chul-Ho Jeong

Keyword(s):

Cell Proliferation ◽

Drug Resistance ◽

Drug Repurposing ◽

Synergistic Action ◽

Cancer Drug ◽

Cancer Cell Proliferation ◽

Cancer Drug Resistance ◽

Anti Cancer

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

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