The Impact of Modifying Sunitinib Treatment Scheduling on Renal Cancer Tumor Biology and Resistance

With sunitinib treatment of metastatic renal cell carcinoma, most patients end up developing resistance over time. Recent clinical trials have shown that individualizing treatment protocols could delay resistance and result in better outcomes. We developed an in vivo xenograft tumor model and compared tumor growth rate, morphological, and transcriptomic differences between alternative and traditional treatment schedules. Our results show that the alternative treatment regime could delay/postpone cancer progression. Additionally, we identified distinct morphological changes in the tumor with alternative and traditional treatments, likely due to the significantly dysregulated signaling pathways between the protocols. Further investigation of the signaling pathways underlying these morphological changes may lead potential therapeutic targets to be used in a combined treatment with sunitinib, which offers promise in postponing/reversing the resistance of sunitinib.

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Impact of RARα and miR-138 on retinoblastoma etoposide resistance

Tumor Biology ◽

10.3233/tub-200072 ◽

2021 ◽

Vol 43 (1) ◽

pp. 11-26

Author(s):

Maike Busch ◽

Natalia Miroschnikov ◽

Jaroslaw Thomas Dankert ◽

Marc Wiesehöfer ◽

Klaus Metz ◽

...

Keyword(s):

Cell Viability ◽

Cell Lines ◽

Cancer Progression ◽

Treated Patient ◽

Luciferase Reporter ◽

Luciferase Reporter Gene ◽

Gene Assay ◽

The Impact

BACKGROUND: Retinoblastoma (RB) is the most common childhood eye cancer. Chemotherapeutic drugs such as etoposide used in RB treatment often cause massive side effects and acquired drug resistances. Dysregulated genes and miRNAs have a large impact on cancer progression and development of chemotherapy resistances. OBJECTIVE: This study was designed to investigate the involvement of retinoic acid receptor alpha (RARα) in RB progression and chemoresistance as well as the impact of miR-138, a potential RARα regulating miRNA. METHODS: RARα and miR-138 expression in etoposide resistant RB cell lines and chemotherapy treated patient tumors compared to non-treated tumors was revealed by Real-Time PCR. Overexpression approaches were performed to analyze the effects of RARα on RB cell viability, apoptosis, proliferation and tumorigenesis. Besides, we addressed the effect of miR-138 overexpression on RB cell chemotherapy resistance. RESULTS: A binding between miR-138 and RARα was shown by dual luciferase reporter gene assay. The study presented revealed that RARα is downregulated in etoposide resistant RB cells, while miR-138 is endogenously upregulated. Opposing RARα and miR-138 expression levels were detectable in chemotherapy pre-treated compared to non-treated RB tumor specimen. Overexpression of RARα increases apoptosis levels and reduces tumor cell growth of aggressive etoposide resistant RB cells in vitro and in vivo. Overexpression of miR-138 in chemo-sensitive RB cell lines partly enhances cell viability after etoposide treatment. CONCLUSIONS: Our findings show that RARα acts as a tumor suppressor in retinoblastoma and is downregulated upon etoposide resistance in RB cells. Thus, RARα may contribute to the development and progression of RB chemo-resistance.

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Anti-Cancer Properties of Theaflavins

Molecules ◽

10.3390/molecules26040987 ◽

2021 ◽

Vol 26 (4) ◽

pp. 987

Author(s):

Eric J. O’Neill ◽

Deborah Termini ◽

Alexandria Albano ◽

Evangelia Tsiani

Keyword(s):

Signaling Pathways ◽

Cancer Progression ◽

Treatment Strategies ◽

B Cell Lymphoma ◽

Black Tea ◽

Phosphorylated Akt ◽

Phenolic Components ◽

Anti Cancer

Cancer is a disease characterized by aberrant proliferative and apoptotic signaling pathways, leading to uncontrolled proliferation of cancer cells combined with enhanced survival and evasion of cell death. Current treatment strategies are sometimes ineffective in eradicating more aggressive, metastatic forms of cancer, indicating the need to develop novel therapeutics targeting signaling pathways which are essential for cancer progression. Historically, plant-derived compounds have been utilized in the production of pharmaceuticals and chemotherapeutic compounds for the treatment of cancer, including paclitaxel and docetaxel. Theaflavins, phenolic components present in black tea, have demonstrated anti-cancer potential in cell cultures in vitro and in animal studies in vivo. Theaflavins have been shown to inhibit proliferation, survival, and migration of many cancer cellswhile promoting apoptosis. Treatment with theaflavins has been associated with increased levels of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspases-3, -7, -8, and -9, all markers of apoptosis, and increased expression of the proapoptotic marker Bcl-2-associated X protein (Bax) and concomitant reduction in the antiapoptotic marker B-cell lymphoma 2 (Bcl-2). Additionally, theaflavin treatment reduced phosphorylated Akt, phosphorylated mechanistic target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), and c-Myc levels with increased expression of the tumour suppressor p53. This review summarizes the current in vitro and in vivo evidence available investigating the anti-cancer effects of theaflavins across various cancer cell lines and animal models.

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KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

Cancer Biomarkers ◽

10.3233/cbm-201045 ◽

2021 ◽

pp. 1-15

Author(s):

Ping Xu ◽

Xiao Mo ◽

Ruixue Xia ◽

Long Jiang ◽

Chengfei Zhang ◽

...

Keyword(s):

Potassium Channels ◽

Lung Adenocarcinoma ◽

Potassium Channel ◽

Signaling Pathways ◽

Epithelial To Mesenchymal Transition ◽

Tumor Biology ◽

Erk Signaling ◽

Mesenchymal Transition

BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

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Diet, Obesity, and Cancer Progression: Are Adipocytes the Link?

Lipid Insights ◽

10.4137/lpi.s10871 ◽

2013 ◽

Vol 6 ◽

pp. LPI.S10871 ◽

Cited By ~ 11

Author(s):

Paul Toren ◽

Benjamin C. Mora ◽

Vasundara Venkateswaran

Keyword(s):

Tumor Microenvironment ◽

Cancer Progression ◽

Tumor Biology ◽

Model Systems ◽

In Vivo Model ◽

Diet Induced Obesity ◽

Breast And Prostate Cancer ◽

Obesity And Cancer

Obesity has been linked to more aggressive characteristics of several cancers, including breast and prostate cancer. Adipose tissue appears to contribute to paracrine interactions in the tumor microenvironment. In particular, cancer-associated adipocytes interact reciprocally with cancer cells and influence cancer progression. Adipokines secreted from adipocytes likely form a key component of the paracrine signaling in the tumor microenvironment. In vitro coculture models allow for the assessment of specific adipokines in this interaction. Furthermore, micronutrients and macronutrients present in the diet may alter the secretion of adipokines from adipocytes. The effect of dietary fat and specific fatty acids on cancer progression in several in vivo model systems and cancer types is reviewed. The more common approaches of caloric restriction or diet-induced obesity in animal models establish that such dietary changes modulate tumor biology. This review seeks to explore available evidence regarding how diet may modulate tumor characteristics through changes in the role of adipocytes in the tumor microenvironment.

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Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.772510 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sareshma Sudhesh Dev ◽

Syafiq Asnawi Zainal Abidin ◽

Reyhaneh Farghadani ◽

Iekhsan Othman ◽

Rakesh Naidu

Keyword(s):

Signaling Pathways ◽

Cancer Progression ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Surface Proteins ◽

Downstream Signaling ◽

Anti Cancer ◽

Rtk Inhibitors

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

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Curcumin inhibits cancer progression through regulating expression of microRNAs

Tumor Biology ◽

10.1177/1010428317691680 ◽

2017 ◽

Vol 39 (2) ◽

pp. 101042831769168 ◽

Cited By ~ 25

Author(s):

Siying Zhou ◽

Sijie Zhang ◽

Hongyu Shen ◽

Wei Chen ◽

Hanzi Xu ◽

...

Keyword(s):

Signaling Pathways ◽

Cancer Progression ◽

Noncoding Rna ◽

Target Genes ◽

Therapeutic Potential ◽

Tumor Biology ◽

Multiple Cancer ◽

Small Noncoding Rna ◽

Cancer Agent ◽

Regulation Of Cell Cycle

Curcumin, a major yellow pigment and spice in turmeric and curry, is a powerful anti-cancer agent. The anti-tumor activities of curcumin include inhibition of tumor proliferation, angiogenesis, invasion and metastasis, induction of tumor apoptosis, increase of chemotherapy sensitivity, and regulation of cell cycle and cancer stem cell, indicating that curcumin maybe a strong therapeutic potential through modulating various cancer progression. It has been reported that microRNAs as small noncoding RNA molecules are related to cancer progression, which can be regulated by curcumin. Dysregulated microRNAs play vital roles in tumor biology via regulating expressions of target genes and then influencing multiple cancer-related signaling pathways. In this review, we focused on the inhibition effect of curcumin on various cancer progression by regulating expression of multiple microRNAs. Curcumin-induced dysregulation of microRNAs may activate or inactivate a set of signaling pathways, such as Akt, Bcl-2, PTEN, p53, Notch, and Erbb signaling pathways. A better understanding of the relation between curcumin and microRNAs may provide a potential therapeutic target for various cancers.

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MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy

Biomolecules ◽

10.3390/biom10071040 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1040 ◽

Cited By ~ 3

Author(s):

Milad Ashrafizadeh ◽

Hui Li Ang ◽

Ebrahim Rahmani Moghadam ◽

Shima Mohammadi ◽

Vahideh Zarrin ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Therapy ◽

Signaling Pathways ◽

Tumor Cells ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Migration And Invasion ◽

Circular Rnas ◽

Mesenchymal Transition ◽

The Impact

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

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A combined treatment approach for cachexia and cancer-related anemia in advanced cancer patients: A randomized placebo-controlled trial.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.31_suppl.189 ◽

2014 ◽

Vol 32 (31_suppl) ◽

pp. 189-189 ◽

Cited By ~ 2

Author(s):

Clelia Madeddu ◽

Giulia Gramignano ◽

Luciana Tanca ◽

Maria Cristina Cherchi ◽

Carlo Aurelio Floris ◽

...

Keyword(s):

Energy Metabolism ◽

Cancer Patients ◽

Advanced Cancer ◽

Cancer Progression ◽

Iron Metabolism ◽

Combined Treatment ◽

Advanced Cancer Patients ◽

Tnf Α ◽

Cancer Related Anemia ◽

The Impact

189 Background: Cancer progression is characterized by specific energy metabolism alterations and by symptoms including fatigue, anorexia, nausea, depression, which results in cachexia syndrome and compromised quality of life (QL). This condition is often associated to anemia (cancer-related anemia, CRA), which negatively impacts patient QL and disease outcome. Methods: Adult advanced cancer patients with cachexia (i.e., weight loss > 5% in the previous 6 months) and CRA were randomly assigned (1:1 by computer generated list) to receive 3 months of a combined approach consisting of celecoxib (200 mg/day), L-carnitine (2 g/day), curcumin (Meriva) (4 g/day) and lactoferrin (200 mg/day) or placebo. The rationale for selecting these agents was: L-carnitine for modulating cell energy metabolism; celecoxib for counteracting inflammation, which is a key feature of cachexia; curcumin for its antiinflammatory and antioxidant action, without disregarding its action on the NF-kB and JAK-STAT pathway and the related synthesis of proinflammatory cytokines; lactoferrin for its ability to regulate iron metabolism in anemic cancer patients. Primary endpoints were improvement of lean body mass (LBM), appetite, fatigue and anemia. Additionally, we assessed the impact of treatment on the main metabolic/inflammatory and iron metabolism parameters: C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, leptin, reactive oxygen species (ROS), glutathione peroxidase, serum iron, ferritin, hepcidin and erythropoietin (EPO). Results: From January 2013 to March 2014, 66 patients have been enrolled. The combination arm was more effective than placebo arm in improving body weight, LBM, appetite, fatigue, and anemia. Among secondary parameters IL-6, TNF-α, CRP, ROS, ferritin, hepcidin and EPO decreased, while leptin increased significantly in the combination arm. No significant changes were observed in the placebo arm. Conclusions: To date a standard effective treatment of cancer cachexia is lacking. Our combined multitargeted approach was able to improve the nutritional and immunometabolic alterations of cachexia, ameliorate patient QL and correct CRA.

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Independence of HIF1a and androgen signaling pathways in prostate cancer

10.1101/848424 ◽

2019 ◽

Author(s):

Maxine GB Tran ◽

Becky AS Bibby ◽

Lingjian Yang ◽

Franklin Lo ◽

Anne Warren ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Growth ◽

Signaling Pathways ◽

Cancer Progression ◽

Poor Prognosis ◽

Therapeutic Strategy ◽

Promote Tumor Growth ◽

Elevated Expression

AbstractAndrogen signaling drives prostate cancer progression and is a therapeutic target. Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.

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P110α and P110δ catalytic subunits of PI3 kinase regulate lysophosphatidylcholine-induced TRPC6 externalization

AJP Cell Physiology ◽

10.1152/ajpcell.00425.2020 ◽

2021 ◽

Author(s):

Pinaki Chaudhuri ◽

Andrew H. Smith ◽

Priya Putta ◽

Linda M. Graham ◽

Michael A. Rosenbaum

Keyword(s):

Signaling Pathways ◽

Intracellular Signaling ◽

Transient Receptor Potential ◽

Oxidation Products ◽

In Vivo Studies ◽

Subsequent Increase ◽

Lipid Oxidation Products ◽

The Impact

Lipid oxidation products, including lysophosphatidylcholine (lysoPC) inhibit endothelial cell (EC) migration in vitro and impair EC healing of arterial injuries in vivo, in part by activating phosphatidylinositol 3-kinase (PI3K), which increases the externalization of canonical transient receptor potential 6 (TRPC6) channels and the subsequent increase in intracellular calcium. Inhibition of PI3K is a potential method to decrease TRPC6 activation and restore migration, but PI3K is involved in multiple intracellular signaling pathways and has multiple downstream effectors. The goal of this study is to identify the specific p110 catalytic subunit isoforms responsible for lysoPC-induced TRPC6 externalization to identify a target for intervention while minimizing impact on alternative signaling pathways. Down-regulation of the p110α and p110δ isoforms, but not the p110β or p110γ isoforms, with small interfering RNA significantly decreased phosphatidylinositol (3,4,5)-trisphosphate production and TRPC6 externalization, and significantly improved EC migration in the presence of lysoPC. These results identify an additional role of p110α in EC and reveal for the first time a specific role of p110δ in EC, providing a foundation for subsequent in vivo studies to investigate the impact of p110 isoform inhibition on arterial healing after injury.

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