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New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0

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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 September 2020) | Viewed by 41518

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Prof. Dr. Chiara Riganti

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Guest Editor

Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
Interests: multidrug resistance; immune-resistance; immune-evasion; cancer metabolism
Special Issues, Collections and Topics in MDPI journals

Dr. Marialessandra Contino

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Guest Editor

Department of Pharmacy, University of Bari, Bari, Italy
Interests: pharmacological and medicinal chemist strategies to reverse multidrug resistance (ABC-transporters related); collateral sensitivity; cannabinoid receptors in cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Up to 70% of solid and hematological tumors are chemoresistant at diagnosis and/or become resistant during chemotherapy, developing a multiple cross-resistance towards drugs unrelated in structure and activity, termed “multidrug resistance” (MDR). Besides being resistant to chemotherapy, MDR cells are often simultaneously resistant to multiple stresses, such as radiotherapy, hypoxia, nutrient shortage. Of note, MDR cells are also less recognized by the immune system, because they produce immune-suppressive metabolites and poorly raise an anti-tumor adaptive response by the host immune system in response to chemotherapy or radiotherapy. The reasons of this chemo-immune resistance rely on the superior ability of MDR cells to adapt to stressing conditions. Metabolic rewiring and epigenetic events, such as the expression of specific miRNAs or ncRNAs, play a key role in such adaptation.

This Special Issue of IJMS will focus on the latest studies dissecting the molecular linkages between chemoresistance and immune resistance and on new possible chemo-immune sensitizer approaches, including radio–chemotherapy and radio–immune–chemotherapy combinations, metabolic modifiers, epigenetic modulators.

The first Special Issue on this theme was launched in 2019,
https://www.mdpi.com/journal/ijms/special_issues/chemo_immuno_resistance
Given the high success and interest in the readership, IJMS is pleased to re-open submission of manuscript on this crucial aspect of tumor biology.

Dr. Chiara Riganti
Dr. Marialessandra Contino
Guest Editors

Manuscript Submission Information

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Keywords

multidrug resistance (MDR)
stress adaptation
immune resistance
immune evasion
cancer cell metabolism
cancer epigenetics
miRNA
non-coding RNA
radio–chemotherapy
radio–immune–chemotherapy
epigenetic modulators.

Published Papers (10 papers)

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Research

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19 pages, 3489 KiB

Open AccessArticle

Downregulation of miR-506-3p Facilitates EGFR-TKI Resistance through Induction of Sonic Hedgehog Signaling in Non-Small-Cell Lung Cancer Cell Lines

by Inamul Haque, Hameem I. Kawsar, Hannah Motes, Mukut Sharma, Snigdha Banerjee, Sushanta K. Banerjee, Andrew K. Godwin and Chao H. Huang

Int. J. Mol. Sci. 2020, 21(23), 9307; https://doi.org/10.3390/ijms21239307 - 06 Dec 2020

Cited by 19 | Viewed by 4241

Abstract

Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR-targeted tyrosine kinase inhibitors (TKIs). Treatment resistance remains the primary obstacle to the successful treatment of NSCLC. Although drug resistance mechanisms have been studied extensively in NSCLC, the regulation of these mechanisms has not been completely understood. Recently, increasing numbers of microRNAs (miRNAs) are implicated in EGFR-TKI resistance, indicating that miRNAs may serve as novel targets and may hold promise as predictive biomarkers for anti-EGFR therapy. MicroRNA-506 (miR-506) has been identified as a tumor suppressor in many cancers, including lung cancer; however, the role of miR-506 in lung cancer chemoresistance has not yet been addressed. Here we report that miR-506-3p expression was markedly reduced in erlotinib-resistant (ER) cells. We identified Sonic Hedgehog (SHH) as a novel target of miR-506-3p, aberrantly activated in ER cells. The ectopic overexpression of miR-506-3p in ER cells downregulates SHH signaling, increases E-cadherin expression, and inhibits the expression of vimentin, thus counteracting the epithelial–mesenchymal transition (EMT)-mediated chemoresistance. Our results advanced our understanding of the molecular mechanisms underlying EGFR-TKI resistance and indicated that the miR-506/SHH axis might represent a novel therapeutic target for future EGFR mutated lung cancer treatment. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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14 pages, 6332 KiB

Open AccessArticle

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

by Cristina Nieto-Jimenez, Ana Alcaraz-Sanabria, Sandra Martinez-Canales, Veronica Corrales-Sanchez, Juan Carlos Montero, Miguel Burgos, Miriam Nuncia-Cantarero, Atanasio Pandiella, Eva M. Galan-Moya and Alberto Ocaña

Int. J. Mol. Sci. 2020, 21(23), 9034; https://doi.org/10.3390/ijms21239034 - 27 Nov 2020

Cited by 4 | Viewed by 2654

Abstract

Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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27 pages, 18805 KiB

Open AccessArticle

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

by Entaz Bahar, Ji-Ye Kim, Hyun-Soo Kim and Hyonok Yoon

Int. J. Mol. Sci. 2020, 21(20), 7613; https://doi.org/10.3390/ijms21207613 - 15 Oct 2020

Cited by 18 | Viewed by 6774

Abstract

Ovarian cancer (OC) is the most lethal of the gynecologic cancers, and platinum-based treatment is a part of the standard first-line chemotherapy regimen. However, rapid development of acquired cisplatin resistance remains the main cause of treatment failure, and the underlying mechanism of resistance in OC treatment remains poorly understood. Faced with this problem, our aim in this study was to generate cisplatin-resistant (CisR) OC cell models in vitro and investigate the role of epithelial–mesenchymal transition (EMT) transcription factor Twist on acquired cisplatin resistance in OC cell models. To achieve this aim, OC cell lines OV-90 and SKOV-3 were exposed to cisplatin using pulse dosing and stepwise dose escalation methods for a duration of eight months, and a total of four CisR sublines were generated, two for each cell line. The acquired cisplatin resistance was confirmed by determination of 50% inhibitory concentration (IC₅₀) and clonogenic survival assay. Furthermore, the CisR cells were studied to assess their respective characteristics of metastasis, EMT phenotype, DNA repair and endoplasmic reticulum stress-mediated cell death. We found the IC₅₀ of CisR cells to cisplatin was 3–5 times higher than parental cells. The expression of Twist and metastatic ability of CisR cells were significantly greater than those of sensitive cells. The CisR cells displayed an EMT phenotype with decreased epithelial cell marker E-cadherin and increased mesenchymal proteins N-cadherin and vimentin. We observed that CisR cells showed significantly higher expression of DNA repair proteins, X-ray repair cross-complementing protein 1 (XRCC1) and poly (ADP-ribose) polymerases 1 (PARP1), with significantly reduced endoplasmic reticulum (ER) stress-mediated cell death. Moreover, Twist knockdown reduced metastatic ability of CisR cells by suppressing EMT, DNA repair and inducing ER stress-induced cell death. In conclusion, we highlighted the utilization of an acquired cisplatin resistance model to identify the potential role of Twist as a therapeutic target to reverse acquired cisplatin resistance in OC. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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15 pages, 3464 KiB

Open AccessArticle

Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells

by Koh Kitagawa, Kei Moriya, Kosuke Kaji, Soichiro Saikawa, Shinya Sato, Norihisa Nishimura, Tadashi Namisaki, Takemi Akahane, Akira Mitoro and Hitoshi Yoshiji

Int. J. Mol. Sci. 2020, 21(20), 7588; https://doi.org/10.3390/ijms21207588 - 14 Oct 2020

Cited by 11 | Viewed by 2863

Abstract

Cholangiocarcinoma (CCA) is associated with high mortality rates because of its resistance to conventional gemcitabine-based chemotherapy. Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reportedly exert anti-cancer effects in CCA and lower the risk of CCA; however, the underlying mechanism of these effects remains unclear. The proliferative and oncogenic activities of the transcriptional co-activator Yes-associated protein (YAP) are driven by its association with the TEA domain (TEAD) of transcription factors; thereby, upregulating genes that promote cell growth, inhibit apoptosis, and confer chemoresistance. This study investigated the effects of atorvastatin in combination with gemcitabine on the progression of human CCA associated with YAP oncogenic regulation. Both atorvastatin and gemcitabine concentration-dependently suppressed the proliferation of HuCCT-1 and KKU-M213 human CCA cells. Moreover, both agents induced cellular apoptosis by upregulating the pro-apoptotic marker BAX and downregulating the anti-apoptotic markers MCL1 and BCL2. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes CTGF, CYR61, ANKRD1, and MFAP5 in both CCA cell lines. A xenograft tumor growth assay indicated that atorvastatin and gemcitabine potently repressed human CCA cell-derived subcutaneous tumor growth by inhibiting YAP nuclear translocation and TEAD transcriptional activation. Notably, the anti-cancer effects of the individual agents were significantly enhanced in combination. These results indicate that gemcitabine plus atorvastatin could serve as a potential novel treatment option for CCA. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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19 pages, 4345 KiB

Open AccessArticle

Combinatory Treatment with miR-7-5p and Drug-Loaded Cubosomes Effectively Impairs Cancer Cells

by Ewa Gajda, Marlena Godlewska, Zenon Mariak, Ewa Nazaruk and Damian Gawel

Int. J. Mol. Sci. 2020, 21(14), 5039; https://doi.org/10.3390/ijms21145039 - 17 Jul 2020

Cited by 34 | Viewed by 3487

Abstract

Background: Multidrug resistance (MDR) is an emerging problem in the treatment of cancer. Therefore, there is a necessity for novel strategies that would sensitize tumor cells to the administered chemotherapeutics. One of the innovative approaches in fighting drug-resistant tumors is the treatment of cancer with microRNA (miRNA), or the use of cubosomes (lipid nanoparticles) loaded with drugs. Here, we present a study on a novel approach, which combines both tools. Methods: Cubosomes loaded with miR-7-5p and chemotherapeutics were developed. The effects of drug- and miRNA-loaded vehicles on glioma- (A172, T98G), papillary thyroid- (TPC-1) and cervical carcinoma-derived (HeLa) cells were analyzed using molecular biology techniques, including quantitative real-time PCR, MTS-based cell proliferation test, flow cytometry and spheroids formation assay. Results: The obtained data indicate that miR-7-5p increases the sensitivity of the tested cells to the drug, and that nanoparticles loaded with both miRNA and the drug produce a greater anti-tumor effect in comparison to the free drug treatment. It was found that an increased level of apoptosis in the drug/miRNA co-treated cells is accompanied by an alternation in the expression of the genes encoding for key MDR proteins of the ABC family. Conclusions: Overall, co-administration of miR-7-5p with a chemotherapeutic can be considered a promising strategy, leading to reduced MDR and the induction of apoptosis in cancer cells. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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19 pages, 2557 KiB

Open AccessArticle

Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma

by Martina Godel, Deborah Morena, Preeta Ananthanarayanan, Ilaria Buondonno, Giulio Ferrero, Claudia M. Hattinger, Federica Di Nicolantonio, Massimo Serra, Riccardo Taulli, Francesca Cordero, Chiara Riganti and Joanna Kopecka

Int. J. Mol. Sci. 2020, 21(12), 4500; https://doi.org/10.3390/ijms21124500 - 24 Jun 2020

Cited by 13 | Viewed by 3805

Abstract

Doxorubicin (Dox) is one of the most important first-line drugs used in osteosarcoma therapy. Multiple and not fully clarified mechanisms, however, determine resistance to Dox. With the aim of identifying new markers associated with Dox-resistance, we found a global up-regulation of small nucleolar RNAs (snoRNAs) in human Dox-resistant osteosarcoma cells. We investigated if and how snoRNAs are linked to resistance. After RT-PCR validation of snoRNAs up-regulated in osteosarcoma cells with different degrees of resistance to Dox, we overexpressed them in Dox-sensitive cells. We then evaluated Dox cytotoxicity and changes in genes relevant for osteosarcoma pathogenesis by PCR arrays. SNORD3A, SNORA13 and SNORA28 reduced Dox-cytotoxicity when over-expressed in Dox-sensitive cells. In these cells, GADD45A and MYC were up-regulated, TOP2A was down-regulated. The same profile was detected in cells with acquired resistance to Dox. GADD45A/MYC-silencing and TOP2A-over-expression counteracted the resistance to Dox induced by snoRNAs. We reported for the first time that snoRNAs induce resistance to Dox in human osteosarcoma, by modulating the expression of genes involved in DNA damaging sensing, DNA repair, ribosome biogenesis, and proliferation. Targeting snoRNAs or down-stream genes may open new treatment perspectives in chemoresistant osteosarcomas. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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17 pages, 2271 KiB

Open AccessArticle

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

by Chiara Riganti, Roberta Giampietro, Joanna Kopecka, Costanzo Costamagna, Francesca Serena Abatematteo, Marialessandra Contino and Carmen Abate

Int. J. Mol. Sci. 2020, 21(9), 3333; https://doi.org/10.3390/ijms21093333 - 08 May 2020

Cited by 16 | Viewed by 2611

Abstract

Multidrug resistance (MDR) is the main obstacle to current chemotherapy and it is mainly due to the overexpression of some efflux transporters such as MRP1. One of the most studied strategies to overcome MDR has been the inhibition of MDR pumps through small molecules, but its translation into the clinic unfortunately failed. Recently, a phenomenon called collateral sensitivity (CS) emerged as a new strategy to hamper MDR acting as a synthetic lethality, where the genetic changes developed upon the acquisition of resistance towards a specific agent are followed by the development of hypersensitivity towards a second agent. Among our library of sigma ligands acting as MDR modulators, we identified three compounds, F397, F400, and F421, acting as CS-promoting agents. We deepened their CS mechanisms in the “pure” model of MRP1-expressing cells (MDCK-MRP1) and in MRP1-expressing/drug resistant non-small cell lung cancer cells (A549/DX). The in vitro results demonstrated that (i) the three ligands are highly cytotoxic for MRP1-expressing cells; (ii) their effect is MRP1-mediated; (iii) they increase the cytotoxicity induced by cis-Pt, the therapeutic agent commonly used in the treatment of lung tumors; and (iv) their effect is ROS-mediated. Moreover, a preclinical in vivo study performed in lung tumor xenografts confirms the in vitro findings, making the three CS-promoting agents candidates for a novel therapeutic approach in lung resistant tumors. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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Review

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19 pages, 484 KiB

Open AccessReview

Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma

by Alessandra Ferri, Venturina Stagni and Daniela Barilà

Int. J. Mol. Sci. 2020, 21(14), 4910; https://doi.org/10.3390/ijms21144910 - 11 Jul 2020

Cited by 43 | Viewed by 4754

Abstract

Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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29 pages, 831 KiB

Open AccessReview

Could Protons and Carbon Ions Be the Silver Bullets Against Pancreatic Cancer?

by Camille Huart, Jia-Wei Chen, Benjamin Le Calvé, Carine Michiels and Anne-Catherine Wéra

Int. J. Mol. Sci. 2020, 21(13), 4767; https://doi.org/10.3390/ijms21134767 - 04 Jul 2020

Cited by 9 | Viewed by 3480

Abstract

Pancreatic cancer is a very aggressive cancer type associated with one of the poorest prognostics. Despite several clinical trials to combine different types of therapies, none of them resulted in significant improvements for patient survival. Pancreatic cancers demonstrate a very broad panel of resistance mechanisms due to their biological properties but also their ability to remodel the tumour microenvironment. Radiotherapy is one of the most widely used treatments against cancer but, up to now, its impact remains limited in the context of pancreatic cancer. The modern era of radiotherapy proposes new approaches with increasing conformation but also more efficient effects on tumours in the case of charged particles. In this review, we highlight the interest in using charged particles in the context of pancreatic cancer therapy and the impact of this alternative to counteract resistance mechanisms. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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18 pages, 1601 KiB

Open AccessReview

Drug Sequestration in Lysosomes as One of the Mechanisms of Chemoresistance of Cancer Cells and the Possibilities of Its Inhibition

by Jan Hraběta, Marie Belhajová, Hana Šubrtová, Miguel Angel Merlos Rodrigo, Zbyněk Heger and Tomáš Eckschlager

Int. J. Mol. Sci. 2020, 21(12), 4392; https://doi.org/10.3390/ijms21124392 - 20 Jun 2020

Cited by 41 | Viewed by 5885

Abstract

Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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