Resistance to Apoptosis-Based Cancer TherapyInduction of Non-apoptotic Cell Death to Overcome Chemoresistance

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 17956

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Department of Cell and Cancer Biology, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, Toledo, OH 43614, USA
Interests: chemokine receptors; chemotaxis; cap-dependent mRNA translation in cancer; eukaryotic translation initiation factors, eIF4A1, metastasis; breast cancer; pancreatic cancer; precision medicine/targeted therapy; small molecule inhibitors
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1. Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA
2. Department of Pharmacology, Vanderbilt University, Nashville, TN 37209, USA
Interests: biomarkers; solid-organ transplantation; inflammatory cytokines; cancer immunology; advanced drug delivery
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Office for Research and Innovation, Meharry Medical College, Nashville, TN 37208, USA
Interests: regulation of lymphocyte crosstalk; tumor immunology; cancer immunotherapy; T cell and NK cell biology; neuroimmunology
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College of Pharmacy, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA
Interests: drug resistance; chemotherapy failure; drug–drug interaction; anticancer drug discovery; novel mechanisms
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Special Issue Information

Dear Colleagues,

Apoptosis is a form of regulated cell death (RCD) that is essential for organogenesis and tissue homeostasis. Apoptotic stimuli can trigger intrinsic and/or extrinsic cell death pathways. In cancer patients, apoptotic induction by neoadjuvant chemotherapy, biological therapies, and/or radiotherapy can result in cancer cell death. However, cancer cells can swiftly adapt and become refractory to apoptotic therapies, resulting in clinical resistance to apoptosis. Drug resistance or minimal residual disease contributes to the development of aggressive primary tumors and increases the propensity for metastasis to sentinel lymph nodes, visceral organs, and bones. The ensuing therapy failure decreases the overall survival and the quality of life for the patients with metastatic tumors. In order to overcome this resistance to apoptosis for neoadjuvant chemotherapy or any targeted therapy, alternative forms of RCD have been proposed for induction in apoptosis-resistant cancer cells. These include necroptosis, autophagy, ferroptosis, pyroptosis, and methuosis, some of which could be relevant as immunogenic cell death. These alternative forms of RCD can be induced singly or in combination, and may help balance the immune checkpoint inhibition and/or overall immune response. By employing transformative and transdisciplinary approaches to induce non-apoptotic forms of tumor cell death, we may pave the way for the development of novel anticancer therapies with the hope of improving patient longevity. For this Special Issue, we welcome the submission of original research articles, reviews, communication, commentary, clinical trials, methods, and perspectives that deal with biomarkers/pharmacological/biological/genetic or epigenetic interventions within the broad scope of induction of non-apoptotic cell death to overcome chemoresistance.

Dr. Dayanidhi Raman
Dr. Venkataswarup Tiriveedhi
Dr. Anil Shanker
Dr. Amit K. Tiwari
Guest Editors

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Keywords

  • apoptosis
  • non-apoptotic cell death
  • chemoresistance
  • tumor cell death
  • regulated cell death (RCD)

Published Papers (6 papers)

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Research

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19 pages, 2622 KiB  
Article
A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia
by José M. Carbó, Josep M. Cornet-Masana, Laia Cuesta-Casanovas, Jennifer Delgado-Martínez, Antònia Banús-Mulet, Lise Clément-Demange, Carme Serra, Juanlo Catena, Amadeu Llebaria, Jordi Esteve and Ruth M. Risueño
Cancers 2023, 15(6), 1912; https://doi.org/10.3390/cancers15061912 - 22 Mar 2023
Cited by 3 | Viewed by 1939
Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the [...] Read more.
Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+–TFEB–MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias. Full article
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16 pages, 3575 KiB  
Article
DHODH Inhibition Exerts Synergistic Therapeutic Effect with Cisplatin to Induce Ferroptosis in Cervical Cancer through Regulating mTOR Pathway
by Mengying Jiang, Yizuo Song, Hejing Liu, Yanshan Jin, Ruyi Li and Xueqiong Zhu
Cancers 2023, 15(2), 546; https://doi.org/10.3390/cancers15020546 - 16 Jan 2023
Cited by 9 | Viewed by 3221
Abstract
Ferroptosis exhibits a potent antitumor effect and dihydroorotate dehydrogenase (DHODH) has recently been identified as a novel ferroptosis defender. However, the role of DHODH inhibition in cervical cancer cells is unclear, particularly in synergy with cisplatin via ferroptosis. Herein, shRNA and brequinar were [...] Read more.
Ferroptosis exhibits a potent antitumor effect and dihydroorotate dehydrogenase (DHODH) has recently been identified as a novel ferroptosis defender. However, the role of DHODH inhibition in cervical cancer cells is unclear, particularly in synergy with cisplatin via ferroptosis. Herein, shRNA and brequinar were used to knock down DHODH and directly inhibit DHODH, respectively. Immunohistochemistry and Western blotting assays were performed to measure the expression of proteins. CCK-8 and colony formation assays were employed to assess the cell viability and proliferation. Ferroptosis was monitored through flow cytometry, the malondialdehyde assay kit and JC-1 staining analyses. The nude mouse xenograft model was generated to examine the effect of combination of DHODH inhibition and cisplatin on tumor growth in vivo. The expression of DHODH was increased in cervical cancer tissues. DHODH inhibition inhibited the proliferation and promoted the ferroptosis in cervical cancer cells. A combination of DHODH inhibition and cisplatin synergistically induced both in vitro and in vivo ferroptosis and downregulated the ferroptosis defender mTOR pathway. Therefore, the combination of DHODH inhibition and cisplatin exhibits synergistic effects on ferroptosis induction via inhibiting the mTOR pathway could provide a promising way for cervical cancer therapy. Full article
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11 pages, 1668 KiB  
Article
Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin
by Evgeny M. Kirilin, Timur I. Fetisov, Natalia I. Moiseeva, Ekaterina A. Lesovaya, Lidia A. Laletina, Leyla F. Makhmudova, Angelika E. Manikaylo, Liliya Y. Fomina, Denis A. Burov, Beniamin Yu. Bokhyan, Victoria Y. Zinovieva, Alice S. Vilkova, Larisa V. Mekheda, Nikolay A. Kozlov, Alexander M. Scherbakov, Gennady A. Belitsky, Vytas Švedas, Kirill I. Kirsanov and Marianna G. Yakubovskaya
Cancers 2022, 14(7), 1796; https://doi.org/10.3390/cancers14071796 - 1 Apr 2022
Cited by 5 | Viewed by 2666
Abstract
Soft tissue sarcomas (STS) are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Gold standard of chemotherapy for advanced STS includes combinations of Doxorubicin and Ifosfamide or Gemcitabine and Docetaxel. Chemotherapy is [...] Read more.
Soft tissue sarcomas (STS) are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Gold standard of chemotherapy for advanced STS includes combinations of Doxorubicin and Ifosfamide or Gemcitabine and Docetaxel. Chemotherapy is efficient for less than 50% of patients and it is followed by a fast development of drug resistance. Our study was directed to the search of genetic alterations in cancer cells associated with chemoresistance of undifferentiated pleomorphic and synovial sarcomas to the abovementioned genotoxic drugs. We analyzed chemoresistance of cancer cells in vitro using primary STS cultures and performed genetic analysis for the components of apoptotic signaling. In 27% of tumors, we revealed alterations in TP53, ATM, PIK3CB, PIK3R1, NTRK1, and CSF2RB. Cells from STS specimens with found genetic alterations were resistant to Dox, excluding the only one case when TP53 mutation resulted in the substitution Leu344Arg associated with partial oligomerization loss and did not cause total loss of TP53 function. Significant association between alterations in the components of apoptosis signaling and chemoresistance to Dox was found. Our data are important to elaborate further the therapeutic strategy for STS patients with alterations in apoptotic signaling. Full article
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22 pages, 3988 KiB  
Article
VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study
by Silpa Narayanan, Ying-Fang Fan, Nehaben A. Gujarati, Qiu-Xu Teng, Jing-Quan Wang, Chao-Yun Cai, Yuqi Yang, Anirudh J. Chintalapati, Yixiong Lei, Vijaya L. Korlipara and Zhe-Sheng Chen
Cancers 2021, 13(18), 4675; https://doi.org/10.3390/cancers13184675 - 17 Sep 2021
Cited by 6 | Viewed by 2735
Abstract
The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic [...] Read more.
The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers. Full article
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19 pages, 3739 KiB  
Article
A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells
by Diwakar Bastihalli Tukaramrao, Saloni Malla, Siddharth Saraiya, Ross Allen Hanely, Aniruddha Ray, Shikha Kumari, Dayanidhi Raman and Amit K. Tiwari
Cancers 2021, 13(8), 1954; https://doi.org/10.3390/cancers13081954 - 18 Apr 2021
Cited by 12 | Viewed by 3848
Abstract
Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing [...] Read more.
Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing the stimulatory capacity of dendritic cells (DCs), with an IC50 value of 140 nM. TPH104 (5 µM) significantly increased ATP levels in the supernatant and mobilized intracellular calreticulin to the plasma membrane in MDA-MB-231 cells, compared to cells incubated with the vehicle. Incubating MDA-MB-231 cells for 12 h with TPH104 (1–5 µM) significantly increased TNF-α mRNA levels. The supernatants of dying MDAMB-231 cells incubated with TPH104 increased mouse bone marrow-derived DC maturation, the expression of MHC-II and CD86 and the mRNA expression of TNF-α, IL-6 and IL-12. Overall, these results indicate that TPH104 induces immunogenic cell death in TNBC cells, in part, by activating DCs. Full article
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Review

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28 pages, 1519 KiB  
Review
Tackling of Immunorefractory Tumors by Targeting Alternative Immune Checkpoints
by Dharmindra Dulal, Andrew Boring, David Terrero, Tiffany Johnson, Amit K. Tiwari and Dayanidhi Raman
Cancers 2023, 15(10), 2774; https://doi.org/10.3390/cancers15102774 - 16 May 2023
Cited by 5 | Viewed by 2081
Abstract
Physiologically, well known or traditional immune checkpoints (ICs), such as CTLA-4 and PD-1, are in place to promote tolerance to self-antigens and prevent generation of autoimmunity. In cancer, the ICs are effectively engaged by the tumor cells or stromal ells from the tumor [...] Read more.
Physiologically, well known or traditional immune checkpoints (ICs), such as CTLA-4 and PD-1, are in place to promote tolerance to self-antigens and prevent generation of autoimmunity. In cancer, the ICs are effectively engaged by the tumor cells or stromal ells from the tumor microenvironment through expression of cognate ligands for the ICs present on the cell surface of CD8+ T lymphocytes. The ligation of ICs on CD8+ T lymphocytes triggers inhibitory signaling pathways, leading to quiescence or an exhaustion of CD8+ T lymphocytes. This results in failure of immunotherapy. To overcome this, several FDA-approved therapeutic antibodies are available, but the clinical outcome is quite variable due to the resistance encountered through upregulated expression of alternate ICs such as VISTA, LAG-3, TIGIT and TIM-3. This review focuses on the roles played by the traditional as well as alternate ICs and the contribution of associated signaling pathways in generating such resistance to immunotherapy. Combinatorial targeting of traditional and alternate ICs might be beneficial for immune-refractory tumors. Full article
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