Editorial

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3 pages, 322 KiB

Open AccessEditorial

Autophagy in Cancer Progression and Therapeutics

by Kamilla Kantserova and Ilya Ulasov

Int. J. Mol. Sci. 2023, 24(9), 7973; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097973 - 28 Apr 2023

Viewed by 1033

Abstract

Autophagy is a catabolic process that is necessary for cellular homeostasis maintenance [...] Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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Research

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20 pages, 7429 KiB

Open AccessArticle

Pyrimethamine Modulates Interplay between Apoptosis and Autophagy in Chronic Myelogenous Leukemia Cells

by Young Yun Jung, Chulwon Kim, In Jin Ha, Seok-Geun Lee, Junhee Lee, Jae-Young Um and Kwang Seok Ahn

Int. J. Mol. Sci. 2021, 22(15), 8147; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158147 - 29 Jul 2021

Cited by 11 | Viewed by 2252

Abstract

Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor [...] Read more.

Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s). Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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17 pages, 2746 KiB

Open AccessArticle

Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

by Nienke Visser, Harm Jan Lourens, Gerwin Huls, Edwin Bremer and Valerie R. Wiersma

Int. J. Mol. Sci. 2021, 22(5), 2337; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052337 - 26 Feb 2021

Cited by 12 | Viewed by 2848

Abstract

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is [...] Read more.

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease. Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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12 pages, 1566 KiB

Open AccessArticle

Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition

by Ryan N. Montalvo, Vivian Doerr, Oh Sung Kwon, Erin E. Talbert, Jeung-Ki Yoo, Moon-Hyon Hwang, Branden L. Nguyen, Demetra D. Christou, Andreas N. Kavazis and Ashley J. Smuder

Int. J. Mol. Sci. 2020, 21(21), 8105; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218105 - 30 Oct 2020

Cited by 11 | Viewed by 2433

Abstract

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to [...] Read more.

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague–Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5–ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences. Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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Review

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26 pages, 1303 KiB

Open AccessReview

Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma

by Imran Khan, Mohammad Hassan Baig, Sadaf Mahfooz, Moniba Rahim, Busra Karacam, Elif Burce Elbasan, Ilya Ulasov, Jae-June Dong and Mustafa Aziz Hatiboglu

Int. J. Mol. Sci. 2021, 22(3), 1318; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031318 - 28 Jan 2021

Cited by 18 | Viewed by 4573

Abstract

Autophagy is a process essential for cellular energy consumption, survival, and defense mechanisms. The role of autophagy in several types of human cancers has been explicitly explained; however, the underlying molecular mechanism of autophagy in glioblastoma remains ambiguous. Autophagy is thought to be [...] Read more.

Autophagy is a process essential for cellular energy consumption, survival, and defense mechanisms. The role of autophagy in several types of human cancers has been explicitly explained; however, the underlying molecular mechanism of autophagy in glioblastoma remains ambiguous. Autophagy is thought to be a “double-edged sword”, and its effect on tumorigenesis varies with cell type. On the other hand, autophagy may play a significant role in the resistance mechanisms against various therapies. Therefore, it is of the utmost importance to gain insight into the molecular mechanisms deriving the autophagy-mediated therapeutic resistance and designing improved treatment strategies for glioblastoma. In this review, we discuss autophagy mechanisms, specifically its pro-survival and growth-suppressing mechanisms in glioblastomas. In addition, we try to shed some light on the autophagy-mediated activation of the cellular mechanisms supporting radioresistance and chemoresistance in glioblastoma. This review also highlights autophagy’s involvement in glioma stem cell behavior, underlining its role as a potential molecular target for therapeutic interventions. Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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14 pages, 979 KiB

Open AccessReview

Metabolome-Driven Regulation of Adenovirus-Induced Cell Death

by Anastasia Laevskaya, Anton Borovjagin, Peter S. Timashev, Maciej S. Lesniak and Ilya Ulasov

Int. J. Mol. Sci. 2021, 22(1), 464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010464 - 05 Jan 2021

Cited by 3 | Viewed by 3907

Abstract

A viral infection that involves virus invasion, protein synthesis, and virion assembly is typically accompanied by sharp fluctuations in the intracellular levels of metabolites. Under certain conditions, dramatic metabolic shifts can result in various types of cell death. Here, we review different types [...] Read more.

A viral infection that involves virus invasion, protein synthesis, and virion assembly is typically accompanied by sharp fluctuations in the intracellular levels of metabolites. Under certain conditions, dramatic metabolic shifts can result in various types of cell death. Here, we review different types of adenovirus-induced cell death associated with changes in metabolic profiles of the infected cells. As evidenced by experimental data, in most cases changes in the metabolome precede cell death rather than represent its consequence. In our previous study, the induction of autophagic cell death was observed following adenovirus-mediated lactate production, acetyl-CoA accumulation, and ATP release, while apoptosis was demonstrated to be modulated by alterations in acetate and asparagine metabolism. On the other hand, adenovirus-induced ROS production and ATP depletion were demonstrated to play a significant role in the process of necrotic cell death. Interestingly, the accumulation of ceramide compounds was found to contribute to the induction of all the three types of cell death mentioned above. Eventually, the characterization of metabolite analysis could help in uncovering the molecular mechanism of adenovirus-mediated cell death induction and contribute to the development of efficacious oncolytic adenoviral vectors. Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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22 pages, 1344 KiB

Open AccessReview

The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy

by Chul Won Yun, Juhee Jeon, Gyeongyun Go, Jun Hee Lee and Sang Hun Lee

Int. J. Mol. Sci. 2021, 22(1), 179; https://doi.org/10.3390/ijms22010179 - 26 Dec 2020

Cited by 73 | Viewed by 5583

Abstract

Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal [...] Read more.

Autophagy is a delicate intracellular degradation process that occurs due to diverse stressful conditions, including the accumulation of damaged proteins and organelles as well as nutrient deprivation. The mechanism of autophagy is initiated by the creation of autophagosomes, which capture and encapsulate abnormal components. Afterward, autophagosomes assemble with lysosomes to recycle or remove degradative cargo. The regulation of autophagy has bipolar roles in cancer suppression and promotion in diverse cancers. Furthermore, autophagy modulates the features of tumorigenesis, cancer metastasis, cancer stem cells, and drug resistance against anticancer agents. Some autophagy regulators are used to modulate autophagy for anticancer therapy but the dual roles of autophagy limit their application in anticancer therapy, and present as the main reason for therapy failure. In this review, we summarize the mechanisms of autophagy, tumorigenesis, metastasis, cancer stem cells, and resistance against anticancer agents. Finally, we discuss whether targeting autophagy is a promising and effective therapeutic strategy in anticancer therapy. Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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27 pages, 776 KiB

Open AccessReview

Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance

by Jingwen Xu, Nipa H. Patel and David A. Gewirtz

Int. J. Mol. Sci. 2020, 21(23), 8991; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238991 - 26 Nov 2020

Cited by 43 | Viewed by 4940

Abstract

Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is p53, an essential tumor suppressor that is often mutated or lost in many cancer types and implicated in [...] Read more.

Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is p53, an essential tumor suppressor that is often mutated or lost in many cancer types and implicated in early tumorigenesis. Gain of function (GOF) p53 mutations have been implicated in increased susceptibility to drug resistance, by compromising wildtype anti-tumor functions of p53 or modulating key p53 processes that confer chemotherapy resistance, such as autophagy. Autophagy, a cellular survival mechanism, is initially induced in response to chemotherapy and radiotherapy, and its cytoprotective nature became the spearhead of a number of clinical trials aimed to sensitize patients to chemotherapy. However, increased pre-clinical studies have exemplified the multifunctional role of autophagy. Additionally, compartmental localization of p53 can modulate induction or inhibition of autophagy and may play a role in autophagic function. The duality in p53 function and its effects on autophagic function are generally not considered in clinical trial design or clinical therapeutics; however, ample pre-clinical studies suggest they play a role in tumor responses to therapy and drug resistance. Further inquiry into the interconnection between autophagy and p53, and its effects on chemotherapeutic responses may provide beneficial insights on multidrug resistance and novel treatment regimens for chemosensitization. Full article

(This article belongs to the Special Issue Autophagy in Cancer Progression and Therapeutics)

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