Therapeutic integration of signal transduction targeting agents and conventional anti-cancer treatments.

The currently available treatment of cancer patients is based on the use of cytotoxic drugs and/or of ionizing radiations, which have potent antitumor activity, but also cause clinically relevant side effects, since they affect cellular targets that are common to both cancer cells and normal proliferating cells. In the past 20 years, the discoveries on the molecular mechanisms of cancer development and progression have prompted the search for agents which are more selective for cancer cell molecular targets. The possibility of combining conventional cytotoxic drugs with novel agents that specifically interfere with key pathways controlling cancer cell survival, proliferation, invasion and/or metastatic spreading has generated a wide interest. This could be a promising therapeutic approach for several reasons. First, since the cellular targets for these agents and their mechanism(s) of action are different from those of cytotoxic drugs, it is possible for their combination with chemotherapy without cross-resistance. Second, alterations in the expression and/or the activity of genes that regulate mitogenic signals not only can directly cause perturbation of cell growth, but also may affect the sensitivity of cancer cells to conventional chemotherapy and radiotherapy. In this review, we will discuss the biologic bases of the combination of molecular targeted drugs with conventional medical cancer treatments and the available results of the first series of clinical trials in cancer patients.

Download Full-text

The role of coagulation and platelets in colon cancer-associated thrombosis

AJP Cell Physiology ◽

10.1152/ajpcell.00367.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. C264-C273 ◽

Cited By ~ 12

Author(s):

Annachiara Mitrugno ◽

Samuel Tassi Yunga ◽

Joanna L. Sylman ◽

Jevgenia Zilberman-Rudenko ◽

Toshiaki Shirai ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Cell ◽

Platelet Activation ◽

Molecular Mechanisms ◽

Cell Interactions ◽

Coagulation Cascade ◽

Colon Cancer Cells ◽

Cancer Associated Thrombosis

Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.

Download Full-text

Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation

International Journal of Molecular Sciences ◽

10.3390/ijms22084153 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4153

Author(s):

Kutlwano R. Xulu ◽

Tanya N. Augustine

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Antiplatelet Therapy ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cells ◽

Cancer Cell Lines ◽

Breast Cancer Cell Lines

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

Download Full-text

The Rationale for the Combination of Selective EGFR Inhibitors with Cytotoxic Drugs and Radiotherapy

The International Journal of Biological Markers ◽

10.1177/17246008070221s406 ◽

2007 ◽

Vol 22 (1_suppl4) ◽

pp. 47-52 ◽

Cited By ~ 10

Author(s):

G. Tortora ◽

T. Gelardi ◽

F. Ciardiello ◽

R. Bianco

Keyword(s):

Tyrosine Kinases ◽

Apoptotic Cell ◽

Human Cancer ◽

Growth Factor Receptor ◽

Cytotoxic Drugs ◽

Egfr Inhibitors ◽

Metastatic Spread ◽

Cross Resistance ◽

Promising Therapeutic Approach ◽

Wide Range

The epidermal growth factor receptor (EGFR) is frequently overexpressed in a wide range of human tumors; such overexpression often correlates with poor prognosis and worse clinical outcome. It has been demonstrated that the EGFR autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. For these reasons EGFR is one of the most studied and exploited targets for molecular cancer therapy. Two classes of anti-EGFR agents have entered clinical practice: monoclonal antibodies and small molecules targeting receptor tyrosine kinases. The possibility of combining conventional cytotoxic drugs with agents that specifically interfere with key pathways controlling cancer cell survival, proliferation, invasion and/or metastatic spread has generated wide interest. This could be a promising therapeutic approach for several reasons. First, the occurrence of cross-resistance is infrequent since the cellular targets and mechanisms of action of cytotoxic drugs and EGFR antagonists are different. Second, alterations in the expression and/or activity of genes that regulate mitogenic signals may either cause perturbation of cell growth or affect the sensitivity of cancer cells to conventional chemotherapy and radiotherapy. In fact, EGFR inhibitors have shown activity alone and/or in combination with conventional antitumor treatments.

Download Full-text

A Novel 3D Model for Visualization and Tracking of Fibroblast-Guided Directional Cancer Cell Migration

Biology ◽

10.3390/biology9100328 ◽

2020 ◽

Vol 9 (10) ◽

pp. 328

Author(s):

Yihe Zhang ◽

Bingjie Jiang ◽

Meng Huee Lee

Keyword(s):

Cell Migration ◽

Cancer Cells ◽

Cancer Cell ◽

Molecular Mechanisms ◽

Cell Mass ◽

Physical Contact ◽

Physical Interaction ◽

Matrix Remodeling ◽

Cancer Cell Migration ◽

Cell Type

Stromal fibroblasts surrounding cancer cells are a major and important constituent of the tumor microenvironment not least because they contain cancer-associated fibroblasts, a unique fibroblastic cell type that promotes tumorigenicity through extracellular matrix remodeling and secretion of soluble factors that stimulate cell differentiation and invasion. Despite much progress made in understanding the molecular mechanisms that underpin fibroblast–tumor cross-talk, relatively little is known about the way the two cell types interact from a physical contact perspective. In this study, we report a novel three-dimensional dumbbell model that would allow the physical interaction between the fibroblasts and cancer cells to be visualized and monitored by microscopy. To achieve the effect, the fibroblasts and cancer cells in 50% Matrigel suspension were seeded as independent droplets in separation from each other. To allow for cell migration and interaction, a narrow passage of Matrigel causeway was constructed in between the droplets, effectively molding the gel into the shape of a dumbbell. Under time-lapse microscopy, we were able to visualize and image the entire process of fibroblast-guided cancer cell migration event, from initial vessel-like structure formation by the fibroblasts to their subsequent invasion across the causeway, attracting and trapping the cancer cells in the process. Upon prolonged culture, the entire population of fibroblasts eventually infiltrated across the passage and condensed into a spheroid-like cell mass, encapsulating the bulk of the cancer cell population within. Suitable for almost every cell type, our model has the potential for a wider application as it can be adapted for use in drug screening and the study of cellular factors involved in cell–cell attraction.

Download Full-text

Palmatine from Unexplored Rutidea parviflora Showed Cytotoxicity and Induction of Apoptosis in Human Ovarian Cancer Cells

Toxins ◽

10.3390/toxins11040237 ◽

2019 ◽

Vol 11 (4) ◽

pp. 237 ◽

Cited By ~ 1

Author(s):

Okiemute Rosa Johnson-Ajinwo ◽

Alan Richardson ◽

Wen-Wu Li

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Caspase 3 ◽

Ovarian Cancer Cell ◽

Cancer Cell Lines ◽

Cross Resistance ◽

Gas Liquid Chromatography ◽

Ovarian Cancer Cell Lines

Ovarian cancer ranks amongst the deadliest cancers in the gynaecological category of cancers. This research work aims to evaluate in vitro anti-ovarian cancer activities and identify phytochemical constituents of a rarely explored plant species—Rutidea parviflora DC. The aqueous and organic extracts of the plant were evaluated for cytotoxicity using sulforhodamine B assay in four ovarian cancer cell lines and an immortalized human ovarian epithelial (HOE) cell line. The bioactive compounds were isolated and characterized by gas/liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. Caspase 3/7 activity assay, western blotting and flow cytometry were carried out to assess apoptotic effects of active compounds. The extracts/fractions of R. parviflora showed promising anti-ovarian cancer activities in ovarian cancer cell lines. A principal cytotoxic alkaloid was identified as palmatine whose IC50 was determined as 5.5–7.9 µM. Palmatine was relatively selective towards cancer cells as it was less cytotoxic toward HOE cells, also demonstrating interestingly absence of cross-resistance in cisplatin-resistant A2780 cells. Palmatine further induced apoptosis by increasing caspase 3/7 activity, poly-ADP-ribose polymerase cleavage, and annexin V and propidium iodide staining in OVCAR-4 cancer cells. Our studies warranted further investigation of palmatine and R. parviflora extracts in preclinical models of ovarian cancer.

Download Full-text

Thyroid Hormone and P-Glycoprotein in Tumor Cells

BioMed Research International ◽

10.1155/2015/168427 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 16

Author(s):

Paul J. Davis ◽

Sandra Incerpi ◽

Hung-Yun Lin ◽

Heng-Yuan Tang ◽

Thangirala Sudha ◽

...

Keyword(s):

Thyroid Hormone ◽

Cancer Cells ◽

Cancer Cell ◽

Molecular Mechanisms ◽

Efflux Pump ◽

Inhibitory Effect ◽

Chemotherapeutic Agents ◽

Cell Surface Receptor ◽

P Glycoprotein ◽

Surface Receptor

P-glycoprotein (P-gp; multidrug resistance pump 1, MDR1; ABCB1) is a plasma membrane efflux pump that when activated in cancer cells exports chemotherapeutic agents. Transcription of the P-gp gene (MDR1) and activity of the P-gp protein are known to be affected by thyroid hormone. A cell surface receptor for thyroid hormone on integrinαvβ3 also binds tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4) that blocks nongenomic actions of T4and of 3,5,3′-triiodo-L-thyronine (T3) atαvβ3. Covalently bound to a nanoparticle, tetrac as nanotetrac acts at the integrin to increase intracellular residence time of chemotherapeutic agents such as doxorubicin and etoposide that are substrates of P-gp. This action chemosensitizes cancer cells. In this review, we examine possible molecular mechanisms for the inhibitory effect of nanotetrac on P-gp activity. Mechanisms for consideration include cancer cell acidification via action of tetrac/nanotetrac on the Na+/H+exchanger (NHE1) and hormone analogue effects on calmodulin-dependent processes and on interactions of P-gp with epidermal growth factor (EGF) and osteopontin (OPN), apparently viaαvβ3. Intracellular acidification and decreased H+efflux induced by tetrac/nanotetrac via NHE1 is the most attractive explanation for the actions on P-gp and consequent increase in cancer cell retention of chemotherapeutic agent-ligands of MDR1 protein.

Download Full-text

Overview on the Side Effects of Doxorubicin

10.5772/intechopen.94896 ◽

2020 ◽

Author(s):

Chittipolu Ajaykumar

Keyword(s):

Side Effects ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

Cytotoxic Effect ◽

Molecular Mechanisms ◽

Current Understanding ◽

Preventive Strategies ◽

Normal Cells ◽

Dna Strand

Doxorubicin is an anthracycline antibiotic extracted from the bacterium Streptomyces peucetius. Its cytotoxic effect produced by intercalating with DNA causing breakdown of DNA strand which causes cancer cell apoptosis. Despite being an effective anticancer agent it causes several crucial side effects like carditoxicity, neuropathy, hepatotoxicity, nephrotoxicity, alopecia, typhlitis, myelosuppression, neutropenia, anaemia, thrombocytopenia, nausea, and diarrhoea were caused mainly due to the inability to distinguish between cancer cells and normal cells. This chapter mainly focuses on doxorubicin’s side effects, current understanding of the molecular mechanisms, and management and preventive strategies of doxorubicin’s cardiotoxicity during the treatment of various type of cancer.

Download Full-text

S100A2 induces the growth of Calu-6 Lung Cancer Cells via apoptosis inhibition, invasion enhancement and promoting cell division

10.21203/rs.2.17525/v1 ◽

2019 ◽

Author(s):

Ting Wang ◽

Yiqian Liang ◽

Asmitananda Thakur

Keyword(s):

Lung Cancer ◽

Cell Division ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Cell ◽

Cancer Cell Line ◽

Lung Cancer Cell Line ◽

Lung Cancer Cell ◽

Lung Cancer Patients ◽

Apoptosis Inhibition

Abstract Background S100 calcium binding protein A2 (S100A2) has been confirmed to have an abnormal expression in lung cancer and is associated with a better disease-free internal of lung cancer patients. Our previous studies on S100A2 in lung cancer concentrated on the clinical roles of this protein in lung cancer, finding that S100A2 increasingly expressed in the sera, tissues and plural effusion of lung cancer patients. This study emphasizes its value in the lung cancer cell line.Methods We constructed a S100A2 expression lentivirus vector, then transfected it and blank vector into the Calu-6 lung cancer cell line respectively. After the successful transfection, (which was confirmed by RT-PCR and Western-blot), we used MTT, transwell and flow cytometric analysis to compare the differences in cell proliferation, cell migration, cell invasion, cell apoptosis and cell cycle among the three groups (Calu-6, Calu/neo, Calu-6/S100A2).Results Calu-6 lung cancer cells showed a shift from G1 to S phase after being transfected with S100A2, compared with the control groups. Additionally, Calu-6/S1000A2 cells had enhanced abilities of invasion and down-abilities of apoptosis in contrast with the blank groups (P<0.05). However, there were no significant difference among these three group in the cell behaviors of migration and proliferation (P>0.05).Conclusion Our results firstly indicate that S100A2 has a positive influence on the biological characteristics of Calu-6 lung cancer cell line, including cell division, invasion and apoptosis inhibition. It may play a significant role in the genesis and progression of lung cancer.

Download Full-text

The Synergistic Effects of SHR6390 Combined With Pyrotinib on HER2+/HR+ Breast Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.785796 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yukun Wang ◽

Xiang Yuan ◽

Jing Li ◽

Zhiwei Liu ◽

Xinyang Li ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Molecular Mechanisms ◽

Xenograft Model ◽

Cancer Cell Lines ◽

Migration And Invasion ◽

Breast Cancer Cell Lines

HER2+/HR+ breast cancer is a special molecular type of breast cancer. Existing treatment methods are prone to resistance; “precision treatment” is necessary. Pyrotinib is a pan-her kinase inhibitor that can be used in HER2-positive tumors, while SHR6390 is a CDK4/6 inhibitor that can inhibit ER+ breast cancer cell cycle progression and cancer cell proliferation. In cancer cells, HER2 and CDK4/6 signaling pathways could be nonredundant; co-inhibition of both pathways by combination of SHR6390 and pyrotinib may have synergistic anticancer activity on HER2+/HR+ breast cancer. In this study, we determined the synergy of the two-drug combination and underlying molecular mechanisms. We showed that the combination of SHR6390 and pyrotinib synergistically inhibited the proliferation, migration, and invasion of HER2+/HR+ breast cancer cells in vitro. The combination of two drugs induced G1/S phase arrest and apoptosis in HER2+/HR+ breast cancer cell lines. The combination of two drugs prolonged the time to tumor recurrence in the xenograft model system. By second-generation RNA sequencing technology and enrichment analysis of the pyrotinib-resistant cell line, we found that FOXM1 was associated with induced resistance to HER2-targeted therapy. In HER2+/HR+ breast cancer cell lines, the combination of the two drugs could further reduce FOXM1 phosphorylation, thereby enhancing the antitumor effect to a certain extent. These findings suggest that SHR6390 combination with pyrotinib suppresses the proliferation, migration, and invasion of HER2+/HR+ breast cancers through regulation of FOXM1.

Download Full-text

Proximity proteomics identifies cancer cell membrane cis-molecular complex as a potential cancer target

10.1101/455501 ◽

2018 ◽

Author(s):

Norihiro Kotani ◽

Arisa Yamaguchi ◽

Tomoko Ohnishi ◽

Ryusuke Kuwahara ◽

Takanari Nakano ◽

...

Keyword(s):

Lung Cancer ◽

Cell Membrane ◽

Cancer Cells ◽

Cancer Cell ◽

Primary Lung Cancer ◽

Lung Squamous Cell Carcinoma ◽

Multiple Drug ◽

Cancer Treatments ◽

Lung Cancer Patients

ABSTRACTCancer-specific antigens expressed in the cell membrane have been used as targets for several molecular targeted strategies in recent years with remarkable success. To develop more effective cancer treatments, novel targets and strategies for targeted therapies are needed. Here, we examined the cancer cell membrane-resident “cis-bimolecular complex” as a possible cancer target (cis-bimolecular cancer target: BiCAT) using proximity proteomics, a technique that has attracted attention in recent years. BiCATs were detected using a previously developed method, termed the enzyme-mediated activation of radical source (EMARS), to label the components proximal to a given cell membrane molecule. EMARS analysis identified some BiCATs, such as close homolog of L1 (CHL1), fibroblast growth factor 3 (FGFR3) and α2 integrin, which are commonly expressed in mouse primary lung cancer cells and human lung squamous cell carcinoma cells. Analysis of cancer specimens from 55 lung cancer patients revealed that approximately half of patients were positive for these BiCATs. In vitro simulation of effective drug combinations used for multiple drug treatment strategy was performed using reagents targeted to BiCAT molecules. The combination treatment based on BiCAT information moderately suppressed cancer cell proliferation compared with single administration, suggesting that the information about BiCATs in cancer cells is profitable for the appropriate selection of the combination among molecular targeted reagents. Thus, BiCAT has the possibility to make a contribution to several molecular targeted strategies in future.

Download Full-text