Special Issue "Sensitization Strategies in Cancer Treatment"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 September 2018)

Special Issue Editor

Guest Editor
Dr. Ali R. Jazirehi

Department of Surgery, Division of Surgical Oncology, and the Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095, USA
E-Mail
Interests: signal transduction; apoptosis; epigenetics; immunotherapy; melanoma; lymphoma; immune sensitization; chemo-sensitization; resistance

Special Issue Information

Dear Colleauges,

Due to high mortality rates and increasing incidence, cancer research efforts should focus on delineating the molecular basis of tumor resistance to current therapies, which will aid in designing novel strategies or improving the existing ones. Induction of apoptosis is the favored mode of action of most anti-neoplastic chemotherapeutics to eradicate tumors. To avoid apoptosis, tumors assume various mechanisms. For instance, natural apoptosis inhibitors, such as anti-apoptotic Bcl-2 and Inhibitors of Apoptosis (IAP) family members employ different mechanisms to protect tumors against apoptosis induced by anti-cancer agents. Drug-resistance is additionally strengthened by the appearance of the multi-drug resistance (MDR) phenotype following initial chemotherapy administration. 

As dysregulated expression of anti-apoptotic factors contributes to MDR phenotype, drug-resistant tumors may also develop cross-resistance to immune system.  The development of such cross-resistance proposes that drugs and immune- based treatment approaches utilize a common apoptotic machinery. Selective outgrowth of resistant tumors will eventually lead to patients’ demise. Application of high dose chemotherapy and/or combination chemotherapy is restricted due to presence of redundant resistance mechanisms, changes in drugs’ pharmacokinetics, and undesired adverse clinical toxicities.  Ample evidence shows non-toxic agents that interfere with the function of MDR pumps or adversely modulate the cell survival signaling pathways leading to alterations in the expression profile of apoptosis-associated gene products can lead to the generation of a proapoptotic tumor milieu, and can be efficiently used combined with chemo- or immuno-therapy in the clinical treatment of resistant/relapsed tumors.

Despite recent advances in modern clinical oncology (e.g., CAR T cell redirected immunotherapy, immune checkpoint blockade, targeted therapy, etc.) it has become more evident that research and clinical endeavors should focus on determination of cell survival signaling pathways or their apoptosis-resistant down-stream targets tempered by sensitizing agents that avert the resistance of refractory tumors.  Accordingly, the two-signal (functional complementation) model is proposed; short term exposure of tumors to a non-toxic sensitizing agent (e.g., drugs, cytokines) via interference with survival pathways modifies the expression profile of apoptosis-resistance factors, skews the balance towards a proapoptotic phenotype, and remove the inhibitory block in the apoptotic pathway (signal I). Consequently, apoptosis threshold is reduced, thus, tumors become sensitized to the cytotoxic signals delivered by the second agent (e.g., immune effector cells (CTLs, NK cells), biological response modifiers, immunotherapy, chemotherapy) (signal II). Successful application of sensitization approach will substantially reduce (or eliminate) toxic side effects and much lower doses of cytotoxic agents will be required to achieve synergistic apoptosis.

Corroborated by numerous preclinical studies, the functional complementation model confirms that therapeutic agents, possess the ability to directly induce apoptosis, and to modify the gene expression profile and reduce apoptosis threshold, thus, overcoming the acquired or inherent apoptosis-resistance phenotype of refractory/relapsed tumors.

This Special Issue will highlight the power of tumor sensitization to apoptosis, covering both basic and (pre)clinical aspects that advance our understanding and provide rational molecular basis for its utilization in clinical oncology.

Dr. Ali R. Jazirehi
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 papers will be 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. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). 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.

Published Papers (6 papers)

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Research

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Open AccessArticle Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization
Cancers 2018, 10(12), 495; https://doi.org/10.3390/cancers10120495
Received: 17 October 2018 / Revised: 23 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
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Abstract
Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but [...] Read more.
Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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Open AccessArticle NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration and Chemoresistance
Cancers 2018, 10(7), 228; https://doi.org/10.3390/cancers10070228
Received: 3 May 2018 / Revised: 15 June 2018 / Accepted: 20 June 2018 / Published: 10 July 2018
Cited by 5 | PDF Full-text (3900 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our [...] Read more.
Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study, we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer in comparison to normal tissues. The downregulation of NGAL was strongly correlated with both degree of differentiation and stage (I–IV); it can also serve as a prognostic biomarker for oral cancer. Additionally, tobacco carcinogens were found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration; it also induced resistance against cisplatin. Silencing of NGAL activated mammalian target of rapamycin (mTOR)signaling and reduced autophagy by the liver kinase B1 (LKB1)-activated protein kinase (AMPK)-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and matrix metalloproteinase-9 (MMP-9) were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study, it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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Review

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Open AccessFeature PaperReview Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy
Cancers 2018, 10(12), 483; https://doi.org/10.3390/cancers10120483
Received: 30 September 2018 / Revised: 12 November 2018 / Accepted: 21 November 2018 / Published: 4 December 2018
Cited by 4 | PDF Full-text (1809 KB) | HTML Full-text | XML Full-text
Abstract
Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug [...] Read more.
Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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Open AccessReview Sensitization of Cancer Cells to Radiation and Topoisomerase I Inhibitor Camptothecin Using Inhibitors of PARP and Other Signaling Molecules
Cancers 2018, 10(10), 364; https://doi.org/10.3390/cancers10100364
Received: 22 August 2018 / Revised: 24 September 2018 / Accepted: 26 September 2018 / Published: 28 September 2018
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Abstract
Radiation and certain anticancer drugs damage DNA, resulting in apoptosis induction in cancer cells. Currently, the major limitations on the efficacy of such therapies are development of resistance and adverse side effects. Sensitization is an important strategy for increasing therapeutic efficacy while minimizing [...] Read more.
Radiation and certain anticancer drugs damage DNA, resulting in apoptosis induction in cancer cells. Currently, the major limitations on the efficacy of such therapies are development of resistance and adverse side effects. Sensitization is an important strategy for increasing therapeutic efficacy while minimizing adverse effects. In this manuscript, we review possible sensitization strategies for radiation and anticancer drugs that cause DNA damage, focusing especially on modulation of damage repair pathways and the associated reactions. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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Open AccessReview Ionophores: Potential Use as Anticancer Drugs and Chemosensitizers
Cancers 2018, 10(10), 360; https://doi.org/10.3390/cancers10100360
Received: 23 August 2018 / Revised: 13 September 2018 / Accepted: 21 September 2018 / Published: 27 September 2018
Cited by 3 | PDF Full-text (734 KB) | HTML Full-text | XML Full-text
Abstract
Ion homeostasis is extremely important for the survival of both normal as well as neoplastic cells. The altered ion homeostasis found in cancer cells prompted the investigation of several ionophores as potential anticancer agents. Few ionophores, such as Salinomycin, Nigericin and Obatoclax, have [...] Read more.
Ion homeostasis is extremely important for the survival of both normal as well as neoplastic cells. The altered ion homeostasis found in cancer cells prompted the investigation of several ionophores as potential anticancer agents. Few ionophores, such as Salinomycin, Nigericin and Obatoclax, have demonstrated potent anticancer activities against cancer stem-like cells that are considered highly resistant to chemotherapy and responsible for tumor relapse. The preclinical success of these compounds in in vitro and in vivo models have not been translated into clinical trials. At present, phase I/II clinical trials demonstrated limited benefit of Obatoclax alone or in combination with other anticancer drugs. However, future development in targeted drug delivery may be useful to improve the efficacy of these compounds. Alternatively, these compounds may be used as leading molecules for the development of less toxic derivatives. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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Open AccessReview Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAFV600E-Specific Inhibitor)
Cancers 2018, 10(6), 157; https://doi.org/10.3390/cancers10060157
Received: 13 April 2018 / Revised: 14 May 2018 / Accepted: 23 May 2018 / Published: 24 May 2018
Cited by 1 | PDF Full-text (305 KB) | HTML Full-text | XML Full-text
Abstract
Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MAPK pathway [...] Read more.
Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAFV600E selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAFV600E mutation to establish a new platform for the treatment of melanoma. Full article
(This article belongs to the Special Issue Sensitization Strategies in Cancer Treatment)
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