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Multikinase Inhibitors and Cancer
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Multikinase Inhibitors and Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 24711

Special Issue Editor

Dr. Daniela Grimm

E-Mail Website
Guest Editor
1. Institute of Biomedicine, Aarhus University, Ole Worms Allé 4, 8000 Aarhus, Denmark
2. Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University Magdeburg, Pfälzerplatz 2, 39106 Magdeburg, Germany
Interests: breast cancer; thyroid cancer; prostate cancer; cell biology; gravitational biology; space medicine; tissue engineering; pharmacology; apoptosis; SOX transcription factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is a burden of humankind with high morbidity and mortality. It is the second leading cause of death worldwide and is responsible for an estimated 18.1 million (95% UI: 17.5-18.7 million) new cases of cancer (17 million excluding non-melanoma skin cancer) and 9.6 million (95% UI: 9.3-9.8 million) deaths from cancer (9.5 million excluding non-melanoma skin cancer) worldwide in 2018 (WHO Global Cancer Observatory (GLOBOCAN) 2018).

Tumor formation and progression is a multifactorial process. It involves the dysregulation of cell growth and proliferation, as well as angiogenesis (the formation of new blood vessels), which depend on numerous different signaling pathways each, including kinases as a milestone of function.

In recent times, anticancer therapies by means of multikinase inhibitors (MKI) targeting several kinases have proven promising. MKI inhibit a number of intracellular and cell surface kinases, decreasing tumor growth and replication of different types of cancers. Hence, they have become a new therapeutic option in various cancer types. Over the last few years, new MKI have been developed. These substances appear useful for targeted systemic therapy and have been approved after their efficacy was demonstrated in clinical trials. Currently, MKI are, for example, used in patients with radioiodine (RAI)-refractory advanced metastatic thyroid cancer, and trials have shown clinical benefits for MKI treatment in patients with advanced renal cell cancer, progressive medullary thyroid cancer, breast cancer, gastrointestinal tumors, and others.

However, there are also reports about a broad range of moderate to severe adverse effects associated with treatment. Adverse effects like hypertension may endanger a future successful application of MKI for treating advanced cancers in clinical practice.

This Special Issue shall cover results of studies using animal or cell culture models to investigate the effects of MKI on cancer, applying molecular biological methods. This issue will also publish reports on patients, providing novel mechanistic insights into new aspects that may impact clinical therapy with MKI. In addition, reviews about the current status of new therapy options in different cancer types or about the adverse effects associated with MKI treatment will be published.

Dr. Daniela Grimm
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer
  • multikinase inhibitors
  • animal model
  • cell culture
  • OMICS investigation
  • signal transduction
  • pathways
  • clinical trials
  • adverse effects

Published Papers (4 papers)

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Research

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16 pages, 2546 KiB  
Article
Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential
by Felix Bürkel, Tina Jost, Markus Hecht, Lucie Heinzerling, Rainer Fietkau and Luitpold Distel
Int. J. Mol. Sci. 2020, 21(23), 9321; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239321 - 07 Dec 2020
Cited by 16 | Viewed by 9230
Abstract
CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently [...] Read more.
CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC-115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy. Full article
(This article belongs to the Special Issue Multikinase Inhibitors and Cancer)
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15 pages, 4195 KiB  
Article
Proteasome Inhibitors Suppress ErbB Family Expression through HSP90-Mediated Lysosomal Degradation
by Thanh Kieu Huynh, Chien-Yi Ho, Chi-Hua Tsai, Chien-Kuo Wang, Yun-Ju Chen, Da-Tian Bau, Chih-Yen Tu, Tzong-Shiun Li and Wei-Chien Huang
Int. J. Mol. Sci. 2019, 20(19), 4812; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194812 - 27 Sep 2019
Cited by 8 | Viewed by 3851
Abstract
Although dual EGFR/HER2 tyrosine kinase inhibitor lapatinib has provided effective clinical benefits for HER2-positive breast cancer patients, acquired resistance to this drug remains a major concern. Thus, the development of alternative therapeutic strategies is urgently needed for patients who failed lapatinib treatment. Proteasome [...] Read more.
Although dual EGFR/HER2 tyrosine kinase inhibitor lapatinib has provided effective clinical benefits for HER2-positive breast cancer patients, acquired resistance to this drug remains a major concern. Thus, the development of alternative therapeutic strategies is urgently needed for patients who failed lapatinib treatment. Proteasome inhibitors have been reported to possess high anti-tumor activity to breast cancer cells. Therefore, this study aims to examine whether and how proteasome inhibitor bortezomib can overcome lapatinib resistance. Treatments with several proteasome inhibitors, including Bortezomib, MG132, and proteasome inhibitor I (PSI), as well as the viabilities of both HER2-positive breast cancer cell lines and their lapatinib-resistant clones, were inhibited. Importantly, the expressions of ErbB family were downregulated at both transcriptional and translational levels. Also, our results further indicated that proteasome inhibitors decreased ErbB family expression through lysosomal degradation pathway in a heat shock protein 90 (HSP90)-dependent manner. In this study, our data supported a potential approach to overcome the acquired resistance of HER2-overexpressing breast cancer patients to lapatinib using proteasome inhibitors. Full article
(This article belongs to the Special Issue Multikinase Inhibitors and Cancer)
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12 pages, 2681 KiB  
Article
Chinese Herbal Medicine Ganoderma tsugae Displays Potential Anti-Cancer Efficacy on Metastatic Prostate Cancer Cells
by Wen-Chin Huang, Meng-Shiun Chang, Shih-Yin Huang, Ching-Ju Tsai, Pin-Hung Kuo, Han-Wen Chang, Sheng-Teng Huang, Chao-Lin Kuo, Shou-Lun Lee and Ming-Ching Kao
Int. J. Mol. Sci. 2019, 20(18), 4418; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184418 - 08 Sep 2019
Cited by 15 | Viewed by 3499
Abstract
Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the [...] Read more.
Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the present study, we demonstrated that a traditional Chinese medicine, quality-assured Ganoderma tsugae ethanol extract (GTEE), significantly suppressed cell growth and metastatic capability and caused cell cycle arrest through decreasing expression of cyclins in mPCa cells, PC-3 and DU145 cells. GTEE also induced caspase-dependent apoptosis in mPCa cells. We further showed the potent therapeutic efficacy of GTEE by inhibiting subcutaneous PC-3 tumor growth in a xenograft model. The in vitro and in vivo efficacies on mPCa cells were due to blockade of the PI3K/Akt and MAPK/ERK signaling pathways associated with cancer cell growth, survival and apoptosis. These preclinical data provide the molecular basis for a new potential therapeutic approach toward the treatment of lethal prostate cancer progression. Full article
(This article belongs to the Special Issue Multikinase Inhibitors and Cancer)
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Review

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23 pages, 1306 KiB  
Review
Drug-Induced Hypertension Caused by Multikinase Inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in Renal Cell Carcinoma Treatment
by Nanna Bæk Møller, Cecilie Budolfsen, Daniela Grimm, Marcus Krüger, Manfred Infanger, Markus Wehland and Nils E. Magnusson
Int. J. Mol. Sci. 2019, 20(19), 4712; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194712 - 23 Sep 2019
Cited by 43 | Viewed by 7285
Abstract
This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which [...] Read more.
This paper reviews current treatments for renal cell carcinoma/cancer (RCC) with the multikinase inhibitors (MKIs) sorafenib, sunitinib, lenvatinib and axitinib. Furthermore, it compares these drugs regarding progression-free survival, overall survival and adverse effects (AE), with a focus on hypertension. Sorafenib and sunitinib, which are included in international clinical guidelines as first- and second-line therapy in metastatic RCC, are now being challenged by new-generation drugs like lenvatinib and axitinib. These drugs have shown significant clinical benefits for patients with RCC, but all four induce a variety of AEs. Hypertension is one of the most common AEs related to MKI treatment. Comparing sorafenib, sunitinib and lenvatinib revealed that sorafenib and sunitinib had the same efficacy, but sorafenib was safer to use. Lenvatinib showed better efficacy than sorafenib but worse safety. No trials have yet been completed that compare lenvatinib with sunitinib. Although axitinib promotes slightly higher hypertension rates compared to sunitinib, the overall discontinuation rate and cardiovascular complications are favourable. Although the mean rate of patients who develop hypertension is similar for each drug, some trials have shown large differences, which could indicate that lifestyle and/or genetic factors play an additional role. Full article
(This article belongs to the Special Issue Multikinase Inhibitors and Cancer)
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