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Mechanisms Underlying Cancer Chemoresistance: A Starting Point to Identify New Anticancer Strategies

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: 31 March 2025 | Viewed by 10489

Special Issue Editors

Dr. Barbara Marengo

E-Mail Website
Guest Editor
Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
Interests: chemoresistance; cancer cell metabolism; stress adaptative cell response; cell death; redox homeostasis; redox signalling; antioxidants; glutathione
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Cinzia Domenicotti

E-Mail Website
Guest Editor
Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genoa, Italy
Interests: neuroblastoma; MYC amplification; cancer stemness; drug resistance; protein kinase C; oxidative stress; lipoperoxidation; apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite continuous efforts, chemoresistance remains the biggest challenge in cancer treatment. Several are the mechanisms underlying chemoresistance and considering the high variability of cancer, finding a successful strategy to counteract chemoresistance would seem a utopia. 

A starting point would be to give an overall view that takes into account all physical and molecular tumor features potentially involved in chemotherapy failure in order to identify new markers of chemoresistance that could be monitored in cancer patients and/or modulated in order to improve drug sensitivity.

To highlight this topic, papers focused on the homeostatic adaptive responses that are activated in cancer cells upon therapy and/or describing new therapeutic targets and innovative applications able to counteract the onset of chemoresistance are welcome.

Dr. Barbara Marengo
Prof. Dr. Cinzia Domenicotti
Guest Editors

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Keywords

  • chemoresistance
  • drug uptake
  • cancer stemness
  • redox metabolism
  • antioxidants
  • apoptosis
  • senescence
  • autophagy
  • miRNAs
  • target therapy

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Published Papers (5 papers)

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Research

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16 pages, 5179 KiB  
Article
ULK2 Is a Key Pro-Autophagy Protein That Contributes to the High Chemoresistance and Disease Relapse in FLT3-Mutated Acute Myeloid Leukemia
by Justine Lai, Claire Yang, Chuquan Shang, Will Chen, Michael P. Chu, Joseph Brandwein, Raymond Lai and Peng Wang
Int. J. Mol. Sci. 2024, 25(1), 646; https://doi.org/10.3390/ijms25010646 - 4 Jan 2024
Cited by 1 | Viewed by 1911
Abstract
We recently demonstrated that a small subset of cells in FLT3-mutated acute myeloid leukemia (AML) cell lines exhibit SORE6 reporter activity and cancer stem-like features including chemoresistance. To study why SORE6+ cells are more chemoresistant than SORE6− cells, we hypothesized that [...] Read more.
We recently demonstrated that a small subset of cells in FLT3-mutated acute myeloid leukemia (AML) cell lines exhibit SORE6 reporter activity and cancer stem-like features including chemoresistance. To study why SORE6+ cells are more chemoresistant than SORE6− cells, we hypothesized that these cells carry higher autophagy, a mechanism linked to chemoresistance. We found that cytarabine (Ara-C) induced a substantially higher protein level of LC3B-II in SORE6+ compared to SORE6− cells. Similar observations were made using a fluorescence signal-based autophagy assay. Furthermore, chloroquine (an autophagy inhibitor) sensitized SORE6+ but not SORE6− cells to Ara-C. To decipher the molecular mechanisms underlying the high autophagic flux in SORE6+ cells, we employed an autophagy oligonucleotide array comparing gene expression between SORE6+ and SORE6− cells before and after Ara-C treatment. ULK2 was the most differentially expressed gene between the two cell subsets. To demonstrate the role of ULK2 in conferring higher chemoresistance in SORE6+ cells, we treated the two cell subsets with a ULK1/2 inhibitor, MRT68921. MRT68921 significantly sensitized SORE6+ but not SORE6− cells to Ara-C. Using our in vitro model for AML relapse, we found that regenerated AML cells contained higher ULK2 expression compared to pretreated cells. Importantly, inhibition of ULK2 using MRT68921 prevented in vitro AML relapse. Lastly, using pretreatment and relapsed AML patient bone marrow samples, we found that ULK2 expression was higher in relapsed AML. To conclude, our results supported the importance of autophagy in the relapse of FLT3-mutated AML and highlighted ULK2 in this context. Full article
(This article belongs to the Special Issue Mechanisms Underlying Cancer Chemoresistance: A Starting Point to Identify New Anticancer Strategies)
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9 pages, 251 KiB  
Article
DNA Repair Pathway in Ovarian Cancer Patients Treated with HIPEC
by Dominika Flasarova, Katerina Urban, Ondrej Strouhal, Dusan Klos, Radmila Lemstrova, Pavel Dvorak, Pavel Soucek and Beatrice Mohelnikova-Duchonova
Int. J. Mol. Sci. 2023, 24(10), 8868; https://doi.org/10.3390/ijms24108868 - 17 May 2023
Cited by 3 | Viewed by 1889
Abstract
DNA repair pathways are essential for maintaining genome stability, and understanding the regulation of these mechanisms may help in the design of new strategies for treatments, the prevention of platinum-based chemoresistance, and the prolongation of overall patient survival not only with respect to [...] Read more.
DNA repair pathways are essential for maintaining genome stability, and understanding the regulation of these mechanisms may help in the design of new strategies for treatments, the prevention of platinum-based chemoresistance, and the prolongation of overall patient survival not only with respect to ovarian cancer. The role of hyperthermic intraperitoneal chemotherapy (HIPEC) together with cytoreductive surgery (CRS) and adjuvant systemic chemotherapy is receiving more interest in ovarian cancer (OC) treatment because of the typical peritoneal spread of the disease. The aim of our study was to compare the expression level of 84 genes involved in the DNA repair pathway in tumors and the paired peritoneal metastasis tissue of patients treated with CRS/platinum-based HIPEC with respect to overall patient survival, presence of peritoneal carcinomatosis, treatment response, and alterations in the BRCA1 and BRCA2 genes. Tumors and metastatic tissue from 28 ovarian cancer patients collected during cytoreductive surgery before HIPEC with cisplatin were used for RNA isolation and subsequent cDNA synthesis. Quantitative real-time PCR followed. The most interesting findings of our study are undoubtedly the gene interactions among the genes CCNH, XPA, SLK, RAD51C, XPA, NEIL1, and ATR for primary tumor tissue and ATM, ATR, BRCA2, CDK7, MSH2, MUTYH, POLB, and XRCC4 for metastases. Another interesting finding is the correlation between gene expression and overall survival (OS), where a low expression correlates with a worse OS. Full article
(This article belongs to the Special Issue Mechanisms Underlying Cancer Chemoresistance: A Starting Point to Identify New Anticancer Strategies)
14 pages, 1162 KiB  
Article
APC Loss Prevents Doxorubicin-Induced Cell Death by Increasing Drug Efflux and a Chemoresistant Cell Population in Breast Cancer
by Casey D. Stefanski, Anne Arnason, Sara Maloney, Janna Kotsen, Elizabeth Powers, Jian-Ting Zhang and Jenifer R. Prosperi
Int. J. Mol. Sci. 2023, 24(8), 7621; https://doi.org/10.3390/ijms24087621 - 21 Apr 2023
Cited by 1 | Viewed by 1890
Abstract
Chemoresistance is a major health concern affecting cancer patients. Resistance is multifactorial, with one mechanism being the increased expression of ABC transporters (such as MDR1 and MRP1), which are drug efflux transporters capable of preventing intracellular accumulation of drugs and cell death. Our [...] Read more.
Chemoresistance is a major health concern affecting cancer patients. Resistance is multifactorial, with one mechanism being the increased expression of ABC transporters (such as MDR1 and MRP1), which are drug efflux transporters capable of preventing intracellular accumulation of drugs and cell death. Our lab showed that the loss of Adenomatous Polyposis Coli (APC) caused an intrinsic resistance to doxorubicin (DOX), potentially through an enhanced tumor-initiating cell (TIC) population and the increased activation of STAT3 mediating the expression of MDR1 in the absence of WNT being activated. Here, in primary mouse mammary tumor cells, the loss of APC decreased the accumulation of DOX while increasing the protein levels of MDR1 and MRP1. We demonstrated decreased APC mRNA and protein levels in breast cancer patients compared with normal tissue. Using patient samples and a panel of human breast cancer cell lines, we found no significant trend between APC and either MDR1 or MRP1. Since the protein expression patterns did not show a correlation between the ABC transporters and the expression of APC, we evaluated the drug transporter activity. In mouse mammary tumor cells, the pharmacological inhibition or genetic silencing of MDR1 or MRP1, respectively, decreased the TIC population and increased DOX-induced apoptosis, supporting the use of ABC transporter inhibitors as therapeutic targets in APC-deficient tumors. Full article
(This article belongs to the Special Issue Mechanisms Underlying Cancer Chemoresistance: A Starting Point to Identify New Anticancer Strategies)
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Review

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18 pages, 860 KiB  
Review
Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas
by Paul M. Bingham and Zuzana Zachar
Int. J. Mol. Sci. 2023, 24(18), 14365; https://doi.org/10.3390/ijms241814365 - 21 Sep 2023
Viewed by 1294
Abstract
We review extensive progress from the cancer metabolism community in understanding the specific properties of lipid metabolism as it is redesigned in advanced carcinomas. This redesigned lipid metabolism allows affected carcinomas to make enhanced catabolic use of lipids in ways that are regulated [...] Read more.
We review extensive progress from the cancer metabolism community in understanding the specific properties of lipid metabolism as it is redesigned in advanced carcinomas. This redesigned lipid metabolism allows affected carcinomas to make enhanced catabolic use of lipids in ways that are regulated by oxygen availability and is implicated as a primary source of resistance to diverse treatment approaches. This oxygen control permits lipid catabolism to be an effective energy/reducing potential source under the relatively hypoxic conditions of the carcinoma microenvironment and to do so without intolerable redox side effects. The resulting robust access to energy and reduced potential apparently allow carcinoma cells to better survive and recover from therapeutic trauma. We surveyed the essential features of this advanced carcinoma-specific lipid catabolism in the context of treatment resistance and explored a provisional unifying hypothesis. This hypothesis is robustly supported by substantial preclinical and clinical evidence. This approach identifies plausible routes to the clinical targeting of many or most sources of carcinoma treatment resistance, including the application of existing FDA-approved agents. Full article
(This article belongs to the Special Issue Mechanisms Underlying Cancer Chemoresistance: A Starting Point to Identify New Anticancer Strategies)
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11 pages, 1107 KiB  
Review
The Role of ATP-Binding Cassette Subfamily A in Colorectal Cancer Progression and Resistance
by Latifa Alketbi, Abeer Al-Ali, Iman M. Talaat, Qutayba Hamid and Khuloud Bajbouj
Int. J. Mol. Sci. 2023, 24(2), 1344; https://doi.org/10.3390/ijms24021344 - 10 Jan 2023
Cited by 6 | Viewed by 2600
Abstract
Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic [...] Read more.
Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets. Full article
(This article belongs to the Special Issue Mechanisms Underlying Cancer Chemoresistance: A Starting Point to Identify New Anticancer Strategies)
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