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27 pages, 60821 KiB

Open AccessArticle

Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy

by Tsz Wai Ngai, Gamal Ahmed Elfar, Pearlyn Yeo, Nicholas Phua, Jin Hui Hor, Shuwen Chen, Ying Swan Ho and Chit Fang Cheok

Int. J. Mol. Sci. 2021, 22(19), 10420; https://doi.org/10.3390/ijms221910420 - 27 Sep 2021

Cited by 5 | Viewed by 3793

Abstract

Niclosamide is an oral anthelmintic drug, approved for use against tapeworm infections. Recent studies suggest however that niclosamide may have broader clinical applications in cancers, spurring increased interest in the functions and mechanisms of niclosamide. Previously, we reported that niclosamide targets a metabolic [...] Read more.

Niclosamide is an oral anthelmintic drug, approved for use against tapeworm infections. Recent studies suggest however that niclosamide may have broader clinical applications in cancers, spurring increased interest in the functions and mechanisms of niclosamide. Previously, we reported that niclosamide targets a metabolic vulnerability in p53-deficient tumours, providing a basis for patient stratification and personalised treatment strategies. In the present study, we functionally characterised the contribution of the aniline 4′-NO₂ group on niclosamide to its cellular activities. We demonstrated that niclosamide induces genome-wide DNA damage that is mechanistically uncoupled from its antitumour effects mediated through mitochondrial uncoupling. Elimination of the nitro group in ND-Nic analogue significantly reduced γH2AX signals and DNA breaks while preserving its antitumour mechanism mediated through a calcium signalling pathway and arachidonic acid metabolism. Lipidomics profiling further revealed that ND-Nic-treated cells retained a metabolite profile characteristic of niclosamide-treated cells. Notably, quantitative scoring of drug sensitivity suggests that elimination of its nitro group enhanced the target selectivity of niclosamide against p53 deficiency. Importantly, the results also raise concern that niclosamide may impose a pleiotropic genotoxic effect, which limits its clinical efficacy and warrants further investigation into alternative drug analogues that may ameliorate any potential unwanted side effects. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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18 pages, 3819 KiB

Open AccessArticle

Inhibition of InsP3R with Xestospongin B Reduces Mitochondrial Respiration and Induces Selective Cell Death in T Cell Acute Lymphoblastic Leukemia Cells

by Pablo Cruz, Ulises Ahumada-Castro, Galdo Bustos, Jordi Molgó, Daniela Sauma, Alenka Lovy and César Cárdenas

Int. J. Mol. Sci. 2021, 22(2), 651; https://doi.org/10.3390/ijms22020651 - 11 Jan 2021

Cited by 12 | Viewed by 3485

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy whose chemoresistance and relapse persist as a problem despite significant advances in its chemotherapeutic treatments. Mitochondrial metabolism has emerged as an interesting therapeutic target given its essential role in maintaining bioenergetic and metabolic [...] Read more.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy whose chemoresistance and relapse persist as a problem despite significant advances in its chemotherapeutic treatments. Mitochondrial metabolism has emerged as an interesting therapeutic target given its essential role in maintaining bioenergetic and metabolic homeostasis. T-ALL cells are characterized by high levels of mitochondrial respiration, making them suitable for this type of intervention. Mitochondrial function is sustained by a constitutive transfer of calcium from the endoplasmic reticulum to mitochondria through the inositol 1,4,5-trisphosphate receptor (InsP3R), making T-ALL cells vulnerable to its inhibition. Here, we determine the bioenergetic profile of the T-ALL cell lines CCRF-CEM and Jurkat and evaluate their sensitivity to InsP3R inhibition with the specific inhibitor, Xestospongin B (XeB). Our results show that T-ALL cell lines exhibit higher mitochondrial respiration than non-malignant cells, which is blunted by the inhibition of the InsP3R. Prolonged treatment with XeB causes T-ALL cell death without affecting the normal counterpart. Moreover, the combination of XeB and glucocorticoids significantly enhanced cell death in the CCRF-CEM cells. The inhibition of InsP3R with XeB rises as a potential therapeutic alternative for the treatment of T-ALL. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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Review

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10 pages, 736 KiB

Open AccessReview

Mitochondrial Proteins as Source of Cancer Neoantigens

by Gennaro Prota, Ana Victoria Lechuga-Vieco and Gennaro De Libero

Int. J. Mol. Sci. 2022, 23(5), 2627; https://doi.org/10.3390/ijms23052627 - 27 Feb 2022

Cited by 5 | Viewed by 3137

Abstract

In the past decade, anti-tumour immune responses have been successfully exploited to improve the outcome of patients with different cancers. Significant progress has been made in taking advantage of different types of T cell functions for therapeutic purposes. Despite these achievements, only a [...] Read more.

In the past decade, anti-tumour immune responses have been successfully exploited to improve the outcome of patients with different cancers. Significant progress has been made in taking advantage of different types of T cell functions for therapeutic purposes. Despite these achievements, only a subset of patients respond favorably to immunotherapy. Therefore, there is a need of novel approaches to improve the effector functions of immune cells and to recognize the major targets of anti-tumour immunity. A major hallmark of cancer is metabolic rewiring associated with switch of mitochondrial functions. These changes are a consequence of high energy demand and increased macromolecular synthesis in cancer cells. Such adaptations in tumour cells might generate novel targets of tumour therapy, including the generation of neoantigens. Here, we review the most recent advances in research on the immune response to mitochondrial proteins in different cellular conditions. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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34 pages, 1932 KiB

Open AccessReview

Failure to Guard: Mitochondrial Protein Quality Control in Cancer

by Joseph E. Friedlander, Ning Shen, Aozhuo Zeng, Sovannarith Korm and Hui Feng

Int. J. Mol. Sci. 2021, 22(15), 8306; https://doi.org/10.3390/ijms22158306 - 2 Aug 2021

Cited by 9 | Viewed by 4676

Abstract

Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing [...] Read more.

Mitochondria are energetic and dynamic organelles with a crucial role in bioenergetics, metabolism, and signaling. Mitochondrial proteins, encoded by both nuclear and mitochondrial DNA, must be properly regulated to ensure proteostasis. Mitochondrial protein quality control (MPQC) serves as a critical surveillance system, employing different pathways and regulators as cellular guardians to ensure mitochondrial protein quality and quantity. In this review, we describe key pathways and players in MPQC, such as mitochondrial protein translocation-associated degradation, mitochondrial stress responses, chaperones, and proteases, and how they work together to safeguard mitochondrial health and integrity. Deregulated MPQC leads to proteotoxicity and dysfunctional mitochondria, which contributes to numerous human diseases, including cancer. We discuss how alterations in MPQC components are linked to tumorigenesis, whether they act as drivers, suppressors, or both. Finally, we summarize recent advances that seek to target these alterations for the development of anti-cancer drugs. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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16 pages, 835 KiB

Open AccessReview

The Role of Mitochondria in Carcinogenesis

by Paulina Kozakiewicz, Ludmiła Grzybowska-Szatkowska, Marzanna Ciesielka and Jolanta Rzymowska

Int. J. Mol. Sci. 2021, 22(10), 5100; https://doi.org/10.3390/ijms22105100 - 12 May 2021

Cited by 15 | Viewed by 3652

Abstract

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that [...] Read more.

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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14 pages, 2123 KiB

Open AccessReview

Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids

by Kenza Mamouni, Georgios Kallifatidis and Bal L. Lokeshwar

Int. J. Mol. Sci. 2021, 22(5), 2466; https://doi.org/10.3390/ijms22052466 - 28 Feb 2021

Cited by 15 | Viewed by 4499

Abstract

Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due [...] Read more.

Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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25 pages, 8015 KiB

Open AccessReview

Medicinal Chemistry Targeting Mitochondria: From New Vehicles and Pharmacophore Groups to Old Drugs with Mitochondrial Activity

by Mabel Catalán, Ivonne Olmedo, Jennifer Faúndez and José A. Jara

Int. J. Mol. Sci. 2020, 21(22), 8684; https://doi.org/10.3390/ijms21228684 - 18 Nov 2020

Cited by 14 | Viewed by 5099

Abstract

Interest in tumor cell mitochondria as a pharmacological target has been rekindled in recent years. This attention is due in part to new publications documenting heterogenous characteristics of solid tumors, including anoxic and hypoxic zones that foster cellular populations with differentiating metabolic characteristics. [...] Read more.

Interest in tumor cell mitochondria as a pharmacological target has been rekindled in recent years. This attention is due in part to new publications documenting heterogenous characteristics of solid tumors, including anoxic and hypoxic zones that foster cellular populations with differentiating metabolic characteristics. These populations include tumor-initiating or cancer stem cells, which have a strong capacity to adapt to reduced oxygen availability, switching rapidly between glycolysis and oxidative phosphorylation as sources of energy and metabolites. Additionally, this cell subpopulation shows high chemo- and radioresistance and a high capacity for tumor repopulation. Interestingly, it has been shown that inhibiting mitochondrial function in tumor cells affects glycolysis pathways, cell bioenergy, and cell viability. Therefore, mitochondrial inhibition may be a viable strategy for eradicating cancer stem cells. In this context, medicinal chemistry research over the last decade has synthesized and characterized “vehicles” capable of transporting novel or existing pharmacophores to mitochondrial tumor cells, based on mechanisms that exploit the physicochemical properties of the vehicles and the inherent properties of the mitochondria. The pharmacophores, some of which have been isolated from plants and others, which were synthesized in the lab, are diverse in chemical nature. Some of these molecules are active, while others are prodrugs that have been evaluated alone or linked to mitochondria-targeted agents. Finally, researchers have recently described drugs with well-proven safety and efficacy that may exert a mitochondria-specific inhibitory effect in tumor cells through noncanonical mechanisms. The effectiveness of these molecules may be improved by linking them to mitochondrial carrier molecules. These promising pharmacological agents should be evaluated alone and in combination with classic chemotherapeutic drugs in clinical studies. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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21 pages, 1951 KiB

Open AccessReview

Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy

by Lanfeng Dong, Vinod Gopalan, Olivia Holland and Jiri Neuzil

Int. J. Mol. Sci. 2020, 21(21), 7941; https://doi.org/10.3390/ijms21217941 - 26 Oct 2020

Cited by 83 | Viewed by 7533

Abstract

Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In [...] Read more.

Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In this review, we summarised the major strategies of selective targeting of mitochondria and their functions to combat cancer, including targeting mitochondrial metabolism, the electron transport chain and tricarboxylic acid cycle, mitochondrial redox signalling pathways, and ROS homeostasis. We highlight that delivering anti-cancer drugs into mitochondria exhibits enormous potential for future cancer therapeutic strategies, with a great advantage of potentially overcoming drug resistance. Mitocans, exemplified by mitochondrially targeted vitamin E succinate and tamoxifen (MitoTam), selectively target cancer cell mitochondria and efficiently kill multiple types of cancer cells by disrupting mitochondrial function, with MitoTam currently undergoing a clinical trial. Full article

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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