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Biomedicines
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Killing It Softly–New Approaches to Overcome Cancer Chemoresistance
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Killing It Softly–New Approaches to Overcome Cancer Chemoresistance

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 36710

Special Issue Editors

Dr. Beata Pajak

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Guest Editor
Independent Laboratory of Molecular Biology and Genetics, Kaczkowski Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-183 Warsaw, Poland
Interests: cancer; GBM; anticancer drug discovery; drug development; apoptosis resistance; chemotherapy resistance; cell signaling; bioactive compounds
Special Issues, Collections and Topics in MDPI journals
Dr. Anna Jaśkiewicz

E-Mail Website
Guest Editor
Independent Laboratory of Genetics and Molecular Biology, Kaczkowski Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-183 Warsaw, Poland
Interests: cancer; anticancer agent; histone deacetylases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue, “Killing It Softly–New Approaches to Overcome Cancer Chemoresistance”, will mainly focus on new strategies to eliminate chemoresistant cancer types.

Oncological therapy is an unequal fight with a dangerous opponent who cleverly adapts to changes in the environment, such as activation of the immune response, the presence of cytostatics, and weakening or eliminating their effects. In response to chemotherapeutic drugs or radiotherapy, cancer cells activate several molecular mechanisms that ensure survival and further cancer progression. Examples of mechanisms determining chemo- and radio-resistance include the constitutive activity of survival factors, namely: NF-kB, pSTAT3, expression of MDR multidrug resistance proteins, glycolytic phenotype, shedding of TNF family death-ligand receptors, and many others. Because of the wealth of protective mechanisms, the available chemotherapeutic agents do not meet the need for effective cancer elimination. Therefore, there is an urgent need for the continuous improvement of anti-cancer therapy to reduce the phenomenon of chemoresistance and to effectively attack cancer cells. In the development of medicine, biotechnology, nanomedicine, and molecular biology techniques, anti-cancer therapy progress is also significant.

We cordially invite authors in the field to submit original research or review articles pertaining to this important and fast-progressing field of biomedicine.

Dr. Beata Pajak
Dr. Anna Jaśkiewicz
Guest Editors

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. Biomedicines 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 2600 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.

Keywords

  • cancer
  • chemoresistance
  • anticancer drug
  • sensitization to chemotherapy
  • molecular mechanisms of chemoresistance

Related Special Issue

Published Papers (10 papers)

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Research

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18 pages, 12008 KiB  
Article
Interplay between Partial EMT and Cisplatin Resistance as the Drivers for Recurrence in HNSCC
by Julia Ingruber, Jozsef Dudas, Susanne Sprung, Bianca Lungu and Felicitas Mungenast
Biomedicines 2022, 10(10), 2482; https://doi.org/10.3390/biomedicines10102482 - 05 Oct 2022
Cited by 5 | Viewed by 2342
Abstract
This study aims to investigate the role of partial epithelial to mesenchymal transition (pEMT)-related proteins in modulating Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC). SCC-25 cells were pre-treated with TGF-beta1 followed by transient Krüppel-like Factor 4 (KLF4)-overexpression and Cisplatin treatment. [...] Read more.
This study aims to investigate the role of partial epithelial to mesenchymal transition (pEMT)-related proteins in modulating Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC). SCC-25 cells were pre-treated with TGF-beta1 followed by transient Krüppel-like Factor 4 (KLF4)-overexpression and Cisplatin treatment. Cell growth, cell morphological changes and cell migration were assessed using Juli BR live cell video-microscopy. In addition, Ki-67 and Slug immunostaining and follow-up image cytometric analysis of primary and recurrent HNSCC tumors were performed to evaluate the proliferation index (PI) and the EMT-like phenotype. We observed that proliferating and Slug-positive tumor cells expand after therapy in HNSCC. Subsequently, protein analysis revealed the stabilization of Slug, upregulation of Vimentin and phospho-p38 (p-p38) in Cisplatin-resistant SCC-25 cells. Moreover, KLF4-overexpression contributed to Cisplatin sensitivity by reduction of Slug at the protein level. This work strongly suggests that an pEMT-like pathway is activated in recurrent and Cisplatin-resistant HNSCC. Finally, stable KLF4-overexpression might sensitize HNSCC tumor cells for Cisplatin treatment. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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18 pages, 7964 KiB  
Article
Metformin Enhancement of Therapeutic Effects of 5-Fluorouracil and Oxaliplatin in Colon Cancer Cells and Nude Mice
by Kwan-Ling Yip, Tsen-Ni Tsai, I-Ping Yang, Zhi-Feng Miao, Yen-Cheng Chen, Ching-Chun Li, Wei-Chih Su, Tsung-Kun Chang, Ching-Wen Huang, Hsiang-Lin Tsai, Yung-Sung Yeh and Jaw-Yuan Wang
Biomedicines 2022, 10(5), 955; https://doi.org/10.3390/biomedicines10050955 - 20 Apr 2022
Cited by 5 | Viewed by 2552
Abstract
Studies have demonstrated that metformin has antitumor effects in addition to therapeutic effects on hyperglycemia; however, few studies have explored the effects of metformin in chemotherapy. Therefore, we hypothesized that the administration of metformin would enhance the therapeutic effects of 5-fluorouracil and oxaliplatin [...] Read more.
Studies have demonstrated that metformin has antitumor effects in addition to therapeutic effects on hyperglycemia; however, few studies have explored the effects of metformin in chemotherapy. Therefore, we hypothesized that the administration of metformin would enhance the therapeutic effects of 5-fluorouracil and oxaliplatin (FuOx) to inhibit the growth of colorectal cancer (CRC) cells in vitro and in vivo. The results of our in vitro experiments demonstrated that metformin significantly increased the effects of FuOx with respect to cell proliferation (p < 0.05), colony formation (p < 0.05), and migration (p < 0.01) and induced cell cycle arrest in the G0/G1 phase in HT29 cells and the S phase in SW480 and SW620 cells (p < 0.05). Flow cytometry analysis revealed that metformin combined with FuOx induced late apoptosis (p < 0.05) by mediating mitochondria-related Mcl-1 and Bim protein expression. Furthermore, in vivo, metformin combined with FuOx more notably reduced tumor volume than FuOx or metformin alone did in BALB/c mice (p < 0.05). These findings demonstrate that metformin may act as an adjunctive agent to enhance the chemosensitivity of CRC cells to FuOx. However, further clinical trials are warranted to validate the clinical implications of the findings. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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13 pages, 4013 KiB  
Article
Structure of Some Green Tea Catechins and the Availability of Intracellular Copper Influence Their Ability to Cause Selective Oxidative DNA Damage in Malignant Cells
by Mohd Farhan, Asim Rizvi, Aamir Ahmad, Mohammad Aatif, Mir Waqas Alam and Sheikh Mumtaz Hadi
Biomedicines 2022, 10(3), 664; https://doi.org/10.3390/biomedicines10030664 - 12 Mar 2022
Cited by 12 | Viewed by 2426
Abstract
The possible roles of elevated endogenous copper levels in malignant cells are becoming increasingly understood at a greater depth. Our laboratory has previously demonstrated that tea catechins have the ability to mobilize endogenous copper and undergo a Fenton-like reaction that can selectively damage [...] Read more.
The possible roles of elevated endogenous copper levels in malignant cells are becoming increasingly understood at a greater depth. Our laboratory has previously demonstrated that tea catechins have the ability to mobilize endogenous copper and undergo a Fenton-like reaction that can selectively damage cancer cells. In this communication, by using a diverse panel of malignant cell lines, we demonstrate that the ability of the catechin family [(−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin (EC), and (+)-catechin (C)] to induce apoptosis is dependent on their structure. We further confirm that reactive oxygen species (ROS) are the terminal effectors causing copper-mediated DNA damage. Our studies demonstrate the role of cellular copper transporters CTR1 and ATP7A in the survival dynamics of malignant cells post-EGCG exposure. The results, when considered together with our previous studies, highlight the critical role that copper dynamics and mobilization plays in cancer cells and paves the way for a better understanding of catechins as nutraceutical supplements for malignancies. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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21 pages, 8243 KiB  
Article
Synergistic Anticancer Effect of Glycolysis and Histone Deacetylases Inhibitors in a Glioblastoma Model
by Beata Pająk, Ewelina Siwiak-Niedbalska, Anna Jaśkiewicz, Maja Sołtyka, Rafał Zieliński, Tomasz Domoradzki, Izabela Fokt, Stanisław Skóra and Waldemar Priebe
Biomedicines 2021, 9(12), 1749; https://doi.org/10.3390/biomedicines9121749 - 23 Nov 2021
Cited by 9 | Viewed by 2451
Abstract
Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving [...] Read more.
Over the last decade, we have seen tremendous progress in research on 2-deoxy-D-glucose (2-DG) and its analogs. Clinical trials of 2-DG have demonstrated the challenges of using 2-DG as a monotherapy, due to its poor drug-like characteristics, leading researchers to focus on improving its bioavailability to tissue and organs. Novel 2-DG analogs such as WP1122 and others have revived the old concept of glycolysis inhibition as an effective anticancer strategy. Combined with other potent cytotoxic agents, inhibitors of glycolysis could synergistically eliminate cancer cells. We focused our efforts on the development of new combinations of anticancer agents coupled with 2-DG and its derivatives, targeting glioblastoma, which is in desperate need of novel approaches and therapeutic options and is particularly suited to glycolysis inhibition, due to its reliance on aerobic glycolysis. Herein, we present evidence that a combined treatment of 2-DG analogs and modulation of histone deacetylases (HDAC) activity via HDAC inhibitors (sodium butyrate and sodium valproate) exerts synergistic cytotoxic effects in glioblastoma U-87 and U-251 cells and represents a promising therapeutic strategy. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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17 pages, 6017 KiB  
Article
Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids to Predict Carboplatin Resistance
by Justin W. Gorski, Zhuwei Zhang, J. Robert McCorkle, Jodi M. DeJohn, Chi Wang, Rachel W. Miller, Holly H. Gallion, Charles S. Dietrich, Frederick R. Ueland and Jill M. Kolesar
Biomedicines 2021, 9(8), 1021; https://doi.org/10.3390/biomedicines9081021 - 16 Aug 2021
Cited by 16 | Viewed by 3709
Abstract
The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity [...] Read more.
The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects (p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K–Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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Review

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16 pages, 1643 KiB  
Review
Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies
by Hyunkoo Kang, Haksoo Lee, Dahye Kim, Byeongsoo Kim, JiHoon Kang, Hae Yu Kim, HyeSook Youn and BuHyun Youn
Biomedicines 2022, 10(6), 1308; https://doi.org/10.3390/biomedicines10061308 - 02 Jun 2022
Cited by 19 | Viewed by 3506
Abstract
Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over [...] Read more.
Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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18 pages, 581 KiB  
Review
Looking for the Holy Grail—Drug Candidates for Glioblastoma Multiforme Chemotherapy
by Beata Pająk
Biomedicines 2022, 10(5), 1001; https://doi.org/10.3390/biomedicines10051001 - 26 Apr 2022
Cited by 6 | Viewed by 4343
Abstract
Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most [...] Read more.
Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a ‘breakthrough’. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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31 pages, 908 KiB  
Review
Overcoming Chemotherapy Resistance in Germ Cell Tumors
by Zuzana Országhová, Katarina Kalavska, Michal Mego and Michal Chovanec
Biomedicines 2022, 10(5), 972; https://doi.org/10.3390/biomedicines10050972 - 22 Apr 2022
Cited by 10 | Viewed by 3439
Abstract
Testicular germ cell tumors (GCTs) are highly curable malignancies. Excellent survival rates in patients with metastatic disease can be attributed to the exceptional sensitivity of GCTs to cisplatin-based chemotherapy. This hypersensitivity is probably related to alterations in the DNA repair of cisplatin-induced DNA [...] Read more.
Testicular germ cell tumors (GCTs) are highly curable malignancies. Excellent survival rates in patients with metastatic disease can be attributed to the exceptional sensitivity of GCTs to cisplatin-based chemotherapy. This hypersensitivity is probably related to alterations in the DNA repair of cisplatin-induced DNA damage, and an excessive apoptotic response. However, chemotherapy fails due to the development of cisplatin resistance in a proportion of patients. The molecular basis of this resistance appears to be multifactorial. Tracking the mechanisms of cisplatin resistance in GCTs, multiple molecules have been identified as potential therapeutic targets. A variety of therapeutic agents have been evaluated in preclinical and clinical studies. These include different chemotherapeutics, targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, PARP inhibitors, CDK inhibitors, and anti-CD30 therapy, as well as immune-checkpoint inhibitors, epigenetic therapy, and others. These therapeutics have been used as single agents or in combination with cisplatin. Some of them have shown promising in vitro activity in overcoming cisplatin resistance, but have not been effective in clinical trials in refractory GCT patients. This review provides a summary of current knowledge about the molecular mechanisms of cisplatin sensitivity and resistance in GCTs and outlines possible therapeutic approaches that seek to overcome this chemoresistance. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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18 pages, 914 KiB  
Review
DNA Damage Repair: Predictor of Platinum Efficacy in Ovarian Cancer?
by Dimitra T. Stefanou, Vassilis L. Souliotis, Roubini Zakopoulou, Michalis Liontos and Aristotelis Bamias
Biomedicines 2022, 10(1), 82; https://doi.org/10.3390/biomedicines10010082 - 31 Dec 2021
Cited by 6 | Viewed by 3051
Abstract
Ovarian cancer (OC) is the seventh most common type of cancer in women worldwide. Treatment for OC usually involves a combination of surgery and chemotherapy with carboplatin and paclitaxel. Platinum-based agents exert their cytotoxic action through development of DNA damage, including the formation [...] Read more.
Ovarian cancer (OC) is the seventh most common type of cancer in women worldwide. Treatment for OC usually involves a combination of surgery and chemotherapy with carboplatin and paclitaxel. Platinum-based agents exert their cytotoxic action through development of DNA damage, including the formation of intra- and inter-strand cross-links, as well as single-nucleotide damage of guanine. Although these agents are highly efficient, intrinsic and acquired resistance during treatment are relatively common and remain a major challenge for platinum-based therapy. There is strong evidence to show that the functionality of various DNA repair pathways significantly impacts tumor response to treatment. Various DNA repair molecular components were found deregulated in ovarian cancer, including molecules involved in homologous recombination repair (HRR), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end-joining (NHEJ), and base excision repair (BER), which can be possibly exploited as novel therapeutic targets and sensitive/effective biomarkers. This review attempts to summarize published data on this subject and thus help in the design of new mechanistic studies to better understand the involvement of the DNA repair in the platinum drugs resistance, as well as to suggest new therapeutic perspectives and potential targets. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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90 pages, 3065 KiB  
Review
Targeting Drug Chemo-Resistance in Cancer Using Natural Products
by Wamidh H. Talib, Ahmad Riyad Alsayed, Muna Barakat, May Ibrahim Abu-Taha and Asma Ismail Mahmod
Biomedicines 2021, 9(10), 1353; https://doi.org/10.3390/biomedicines9101353 - 29 Sep 2021
Cited by 51 | Viewed by 7400
Abstract
Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, [...] Read more.
Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, inexpensive, and less toxic sources of chemotherapeutic agents. Additionally, they have multiple mechanisms of action to inhibit various targets involved in the development of drug resistance. In this review, we have summarized the basic research and clinical applications of natural products as possible inhibitors for drug resistance in cancer. The molecular targets and the mechanisms of action of each natural product are also explained. Diverse drug resistance biomarkers were sensitive to natural products. P-glycoprotein and breast cancer resistance protein can be targeted by a large number of natural products. On the other hand, protein kinase C and topoisomerases were less sensitive to most of the studied natural products. The studies discussed in this review will provide a solid ground for scientists to explore the possible use of natural products in combination anticancer therapies to overcome drug resistance by targeting multiple drug resistance mechanisms. Full article
(This article belongs to the Special Issue Killing It Softly–New Approaches to Overcome Cancer Chemoresistance)
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