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Isoliquiritigenin Induces Autophagy and Inhibits Ovarian Cancer Cell Growth

by Hsin-Yuan Chen, Tsui-Chin Huang, Tzong-Ming Shieh, Chi-Hao Wu, Li-Chun Lin and Shih-Min Hsia

Int. J. Mol. Sci. 2017, 18(10), 2025; https://doi.org/10.3390/ijms18102025 - 21 Sep 2017

Cited by 61 | Viewed by 5853

Abstract

Ovarian cancer is one of the commonest gynecologic malignancies, which has a poor prognosis for patients at the advanced stage. Isoliquiritigenin (ISL), an active flavonoid component of the licorice plant, previously demonstrated antioxidant, anti-inflammatory, and tumor suppressive effects. In this study, we investigated [...] Read more.

Ovarian cancer is one of the commonest gynecologic malignancies, which has a poor prognosis for patients at the advanced stage. Isoliquiritigenin (ISL), an active flavonoid component of the licorice plant, previously demonstrated antioxidant, anti-inflammatory, and tumor suppressive effects. In this study, we investigated the antitumor effect of ISL on human ovarian cancer in vitro using the human ovarian cancer cell lines, OVCAR5 and ES-2, as model systems. Our results show that ISL significantly inhibited the viability of cancer cells in a concentration- and time-dependent manner. Flow cytometry analysis indicated that ISL induced G2/M phase arrest. Furthermore, the expression of cleaved PARP, cleaved caspase-3, Bax/Bcl-2 ratio, LC3B-II, and Beclin-1 levels were increased in western blot analysis. To clarify the role of autophagy and apoptosis in the effect of ISL, we used the autophagy inhibitor—3-methyladenine (3-MA) to attenuate the punctate fluorescence staining pattern of the p62/sequestosome 1 (SQSTM1, red fluorescence) and LC3 (green fluorescence) proteins after ISL treatment, and 3-MA inhibited the cytotoxicity of ISL. These findings provide new information about the link between ISL-induced autophagy and apoptosis and suggest that ISL is a candidate agent for the treatment of human ovarian cancer. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessArticle

REP1 Modulates Autophagy and Macropinocytosis to Enhance Cancer Cell Survival

by Jungwon Choi, Hyena Kim, Young Ki Bae and Heesun Cheong

Int. J. Mol. Sci. 2017, 18(9), 1866; https://doi.org/10.3390/ijms18091866 - 28 Aug 2017

Cited by 7 | Viewed by 5221

Abstract

Rab escort protein 1 (REP1), a component of the Rab geranyl-geranyltransferase 2 complex, plays a role in Rab protein recruitment in proper vesicles during vesicle trafficking. In addition to having well-known tissue degenerative phenotypes in the REP1 mutant, REP1 is tightly associated with [...] Read more.

Rab escort protein 1 (REP1), a component of the Rab geranyl-geranyltransferase 2 complex, plays a role in Rab protein recruitment in proper vesicles during vesicle trafficking. In addition to having well-known tissue degenerative phenotypes in the REP1 mutant, REP1 is tightly associated with cancer development and contributes to cell growth and survival. However, the functional mechanism of REP1 in cancer progression is largely uninvestigated. Here, we show that REP1 plays a crucial role in regulating mammalian target of rapamycin (mTOR) signaling and its downstream pathways, as well as autophagy and macropinocytosis, which are essential for cancer cell survival during metabolic stresses including starvation. REP1 small interfering RNA (siRNA) treatment downregulates mTORC1 activity in growing media, but blocks autophagosome formation under nutrient-depleted conditions. In contrast to the mild decrease of lysosomal enzyme activity seen in REP1 depletion, in REP1 knockdown the subcellular localization of lysosomes is altered, and localization of REP1 itself is modulated by intracellular nutrient levels and mTOR activity. Furthermore, REP1 depletion increases macro pinocytosis which may be a feedback mechanism to compensate autophagy inhibition. Concomitant treatment with macropinocytosis inhibitor and REP1siRNAresults in more significant cell death than autophagy blockade with REP1 knockdown. Therefore, REP1-mediated autophagy and lysosomal degradation processes act as novel regulatory mechanisms to support cancer cell survival, which can be further investigated as a potential cancer-targeting pathway. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessArticle

Globular Adiponectin Inhibits Lipopolysaccharide-Primed Inflammasomes Activation in Macrophages via Autophagy Induction: The Critical Role of AMPK Signaling

by Mi Jin Kim, Eun Hye Kim, Nirmala TiliJa Pun, Jae-Hoon Chang, Jung-Ae Kim, Jee-Heon Jeong, Dong Young Choi, Sang-Hyun Kim and Pil-Hoon Park

Int. J. Mol. Sci. 2017, 18(6), 1275; https://doi.org/10.3390/ijms18061275 - 15 Jun 2017

Cited by 41 | Viewed by 8885

Abstract

The inflammasome acts as a key platform for the activation of pro-inflammatory cytokines. Adiponectin exhibits potent anti-inflammatory properties. However, the effect of adiponectin on the modulation of the inflammasome has not been explored. Herein, we show that globular adiponectin (gAcrp) suppressed lipopolysaccharide (LPS)-primed [...] Read more.

The inflammasome acts as a key platform for the activation of pro-inflammatory cytokines. Adiponectin exhibits potent anti-inflammatory properties. However, the effect of adiponectin on the modulation of the inflammasome has not been explored. Herein, we show that globular adiponectin (gAcrp) suppressed lipopolysaccharide (LPS)-primed inflammasomes activation in murine peritoneal macrophages judged by prevention of interleukin-1β (IL-1β) maturation, caspase-1 activation, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, and pyroptotic cell death. Interestingly, pretreatment with 3-methyl adenine, a pharmacological inhibitor of autophagy, abrogated the suppressive effects of gAcrp on IL-1β secretion and caspase-1 activation, indicating the crucial role of autophagy induction in gAcrp-modulation of the inflammasome activation. In addition, inhibition of 5′Adenosine monophaspahate (AMP)-activated protein kinase (AMPK) signaling abolished suppressive effect of gAcrp on inflammasomes activation. Furthermore, autophagy induction or inhibition of the inflammasome activation by gAcrp was not observed in macrophages deficient in AMPK. Taken together, these results indicate that adiponectin inhibits LPS-primed inflammasomes activation in macrophages via autophagy induction and AMPK signaling-dependent mechanisms. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Review

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Open AccessReview

Autophagy Roles in the Modulation of DNA Repair Pathways

by Luciana R. Gomes, Carlos F. M. Menck and Giovana S. Leandro

Int. J. Mol. Sci. 2017, 18(11), 2351; https://doi.org/10.3390/ijms18112351 - 7 Nov 2017

Cited by 103 | Viewed by 11728

Abstract

Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including premature aging, neurodegenerative diseases, and cancer. The interchange between these pathways is complex and it may occur in both directions. Autophagy [...] Read more.

Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including premature aging, neurodegenerative diseases, and cancer. The interchange between these pathways is complex and it may occur in both directions. Autophagy is activated in response to several DNA lesions types and it can regulate different mechanisms and molecules involved in DNA damage response (DDR), such as cell cycle checkpoints, cell death, and DNA repair. Thus, autophagy may modulate DNA repair pathways, the main focus of this review. In addition to the already well-documented autophagy positive effects on homologous recombination (HR), autophagy has also been implicated with other DNA repair mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Given the relevance of these cellular processes, the clinical applications of drugs targeting this autophagy-DNA repair interface emerge as potential therapeutic strategies for many diseases, especially cancer. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Autophagy and Inflammatory Response in the Tumor Microenvironment

by Daniel Ngabire and Gun-Do Kim

Int. J. Mol. Sci. 2017, 18(9), 2016; https://doi.org/10.3390/ijms18092016 - 20 Sep 2017

Cited by 62 | Viewed by 9352

Abstract

Cell death is the last fate of the life cycle of cells. Different pathways involved in cell death are known to date, and are mostly represented by apoptosis, necrosis, and autophagy. Autophagy is one of the most preserved cell death pathways, characterized by [...] Read more.

Cell death is the last fate of the life cycle of cells. Different pathways involved in cell death are known to date, and are mostly represented by apoptosis, necrosis, and autophagy. Autophagy is one of the most preserved cell death pathways, characterized by the elimination of large parts of cytoplasmic components after being consumed by a double-membraned vesicle called an autophagosome. The formed autophagosome then fuses with a lysosome containing degrading enzymes and leads to the digestion of the autophagosome content. Autophagy is triggered by stress-related inducers, and is partially dependent on apoptotic proteins. It plays a major role in cancer, particularly in the tumor microenvironment where it has a paradoxical function in acting as a tumor suppressor and also as a tumor promoter. In the tumor microenvironment, autophagy regulates the differentiation of macrophages into tumor-associated macrophages (TAMs) and fibroblasts into cancer-associated fibroblasts (CAFs). TAMs and CAFs are abundantly present in the tumor microenvironment, and participate actively in tumor growth, tumor invasiveness, and tumor resistance to chemotherapy. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Therapeutic Implications of Autophagy Inducers in Immunological Disorders, Infection, and Cancer

by Sanguine Byun, Eunjung Lee and Ki Won Lee

Int. J. Mol. Sci. 2017, 18(9), 1959; https://doi.org/10.3390/ijms18091959 - 12 Sep 2017

Cited by 49 | Viewed by 6219

Abstract

Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and [...] Read more.

Autophagy is an essential catabolic program that forms part of the stress response and enables cells to break down their own intracellular components within lysosomes for recycling. Accumulating evidence suggests that autophagy plays vital roles in determining pathological outcomes of immune responses and tumorigenesis. Autophagy regulates innate and adaptive immunity affecting the pathologies of infectious, inflammatory, and autoimmune diseases. In cancer, autophagy appears to play distinct roles depending on the context of the malignancy by either promoting or suppressing key determinants of cancer cell survival. This review covers recent developments in the understanding of autophagy and discusses potential therapeutic interventions that may alter the outcomes of certain diseases. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53

by Maria Mrakovcic, Johannes Kleinheinz and Leopold F. Fröhlich

Int. J. Mol. Sci. 2017, 18(9), 1883; https://doi.org/10.3390/ijms18091883 - 31 Aug 2017

Cited by 42 | Viewed by 10281

Abstract

Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading [...] Read more.

Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading to cell cycle arrest, differentiation, and apoptosis. Suberoyl hydroxamic acid (SAHA) is a broad-spectrum histone deacetylase inhibitor (HDACi) suppressing family members in multiple HDAC classes. Increasing evidence indicates that SAHA and other HDACi can, in addition to mitochondria-mediated apoptosis, also promote caspase-independent autophagy. SAHA-induced mTOR inactivation as a major regulator of autophagy activating the remaining autophagic core machinery is by far the most reported pathway in several tumor models. However, the question of which upstream mechanisms regulate SAHA-induced mTOR inactivation that consequently initiate autophagy has been mainly left unexplored. To elucidate this issue, we recently initiated a study clarifying different modes of SAHA-induced cell death in two human uterine sarcoma cell lines which led to the conclusion that the tumor suppressor protein p53 could act as a molecular switch between SAHA-triggered autophagic or apoptotic cell death. In this review, we present current research evidence about HDACi-mediated apoptotic and autophagic pathways, in particular with regard to p53 and its therapeutic implications. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Monitoring and Measuring Autophagy

by Saori R. Yoshii and Noboru Mizushima

Int. J. Mol. Sci. 2017, 18(9), 1865; https://doi.org/10.3390/ijms18091865 - 28 Aug 2017

Cited by 830 | Viewed by 33670

Abstract

Autophagy is a cytoplasmic degradation system, which is important for starvation adaptation and cellular quality control. Recent advances in understanding autophagy highlight its importance under physiological and pathological conditions. However, methods for monitoring autophagic activity are complicated and the results are sometimes misinterpreted. [...] Read more.

Autophagy is a cytoplasmic degradation system, which is important for starvation adaptation and cellular quality control. Recent advances in understanding autophagy highlight its importance under physiological and pathological conditions. However, methods for monitoring autophagic activity are complicated and the results are sometimes misinterpreted. Here, we review the methods used to identify autophagic structures, and to measure autophagic flux in cultured cells and animals. We will also describe the existing autophagy reporter mice that are useful for autophagy studies and drug testing. Lastly, we will consider the attempts to monitor autophagy in samples derived from humans. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Molecular Interactions of Autophagy with the Immune System and Cancer

by Yunho Jin, Yunkyung Hong, Chan Young Park and Yonggeun Hong

Int. J. Mol. Sci. 2017, 18(8), 1694; https://doi.org/10.3390/ijms18081694 - 3 Aug 2017

Cited by 27 | Viewed by 7691

Abstract

Autophagy is a highly conserved catabolic mechanism that mediates the degradation of damaged cellular components by inducing their fusion with lysosomes. This process provides cells with an alternative source of energy for the synthesis of new proteins and the maintenance of metabolic homeostasis [...] Read more.

Autophagy is a highly conserved catabolic mechanism that mediates the degradation of damaged cellular components by inducing their fusion with lysosomes. This process provides cells with an alternative source of energy for the synthesis of new proteins and the maintenance of metabolic homeostasis in stressful environments. Autophagy protects against cancer by mediating both innate and adaptive immune responses. Innate immune receptors and lymphocytes (T and B) are modulated by autophagy, which represent innate and adaptive immune responses, respectively. Numerous studies have demonstrated beneficial roles for autophagy induction as well as its suppression of cancer cells. Autophagy may induce either survival or death depending on the cell/tissue type. Radiation therapy is commonly used to treat cancer by inducing autophagy in human cancer cell lines. Additionally, melatonin appears to affect cancer cell death by regulating programmed cell death. In this review, we summarize the current understanding of autophagy and its regulation in cancer. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

New Insights into the Role of Autophagy in Tumor Immune Microenvironment

by Chia-Jung Li, Wan-Ting Liao, Meng-Yu Wu and Pei-Yi Chu

Int. J. Mol. Sci. 2017, 18(7), 1566; https://doi.org/10.3390/ijms18071566 - 19 Jul 2017

Cited by 39 | Viewed by 8435

Abstract

The tumor microenvironment is a complex system that is affected by various factors, including hypoxia, acidosis, and immune and inflammatory responses, which have significant effects on tumor adhesion, invasion, metastasis, angiogenesis, and autophagy. In this hostile tumor microenvironment, autophagy of tumor cells can [...] Read more.

The tumor microenvironment is a complex system that is affected by various factors, including hypoxia, acidosis, and immune and inflammatory responses, which have significant effects on tumor adhesion, invasion, metastasis, angiogenesis, and autophagy. In this hostile tumor microenvironment, autophagy of tumor cells can promote tumor growth and metastasis. As autophagy is a double-edged sword in tumors, treatment of cancer via regulation of autophagy is extremely complicated. Therefore, understanding the relationship between tumor autophagy and the tumor microenvironment is extremely important. As the immune milieu plays an important role in tumor development, immunotherapy has become a promising form of cancer therapy. A multi-pronged treatment approach using immunotherapy and molecular targets may become the major direction for future cancer treatments. This article reviews existing knowledge regarding the immune factors in the tumor microenvironment and the status of tumor autophagy research. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Clinical Applications of Autophagy Proteins in Cancer: From Potential Targets to Biomarkers

by Svetlana Bortnik and Sharon M. Gorski

Int. J. Mol. Sci. 2017, 18(7), 1496; https://doi.org/10.3390/ijms18071496 - 11 Jul 2017

Cited by 44 | Viewed by 8155

Abstract

Autophagy, a lysosome-mediated intracellular degradation and recycling pathway, plays multiple context-dependent roles in tumorigenesis and treatment resistance. Encouraging results from various preclinical studies have led to the initiation of numerous clinical trials with the intention of targeting autophagy in various cancers. Accumulating knowledge [...] Read more.

Autophagy, a lysosome-mediated intracellular degradation and recycling pathway, plays multiple context-dependent roles in tumorigenesis and treatment resistance. Encouraging results from various preclinical studies have led to the initiation of numerous clinical trials with the intention of targeting autophagy in various cancers. Accumulating knowledge of the particular mechanisms and players involved in different steps of autophagy regulation led to the ongoing discovery of small molecule inhibitors designed to disrupt this highly orchestrated process. However, the development of validated autophagy-related biomarkers, essential for rational selection of patients entering clinical trials involving autophagy inhibitors, is lagging behind. One possible source of biomarkers for this purpose is the autophagy machinery itself. In this review, we address the recent trends, challenges and advances in the assessment of the biomarker potential of clinically relevant autophagy proteins in human cancers. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer

by Hiroshi Tazawa, Shinji Kuroda, Joe Hasei, Shunsuke Kagawa and Toshiyoshi Fujiwara

Int. J. Mol. Sci. 2017, 18(7), 1479; https://doi.org/10.3390/ijms18071479 - 10 Jul 2017

Cited by 44 | Viewed by 9276

Abstract

Oncolytic virotherapy has recently emerged as a promising strategy for inducing tumor-specific cell death. Adenoviruses are widely and frequently used in oncolytic virotherapy. The mechanism of oncolytic adenovirus-mediated tumor suppression involves virus-induced activation of the autophagic machinery in tumor cells. Autophagy is a [...] Read more.

Oncolytic virotherapy has recently emerged as a promising strategy for inducing tumor-specific cell death. Adenoviruses are widely and frequently used in oncolytic virotherapy. The mechanism of oncolytic adenovirus-mediated tumor suppression involves virus-induced activation of the autophagic machinery in tumor cells. Autophagy is a cytoprotective process that produces energy via lysosomal degradation of intracellular components as a physiologic response to various stresses, including hypoxia, nutrient deprivation, and disruption of growth signaling. However, infection with oncolytic adenoviruses induces autophagy and subsequent death of tumor cells rather than enhancing their survival. In this review, we summarize the beneficial role of autophagy in oncolytic adenoviral therapy, including the roles of infection, replication, and cell lysis. Numerous factors are involved in the promotion and inhibition of oncolytic adenovirus-mediated autophagy. Furthermore, recent evidence has shown that oncolytic adenoviruses induce autophagy-related immunogenic cell death (ICD), which enhances the antitumor immune response by inducing the activation of danger signal molecules and thus represents a novel cancer immunotherapy. Understanding the precise role of oncolytic adenovirus-induced autophagy and ICD could enhance the therapeutic potential of oncolytic adenoviral therapy for treating various cancers. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Natural Compounds from Herbs that can Potentially Execute as Autophagy Inducers for Cancer Therapy

by Shian-Ren Lin, Yaw-Syan Fu, May-Jywan Tsai, Henrich Cheng and Ching-Feng Weng

Int. J. Mol. Sci. 2017, 18(7), 1412; https://doi.org/10.3390/ijms18071412 - 1 Jul 2017

Cited by 117 | Viewed by 9549

Abstract

Accumulated evidence indicates that autophagy is a response of cancer cells to various anti-cancer therapies. Autophagy is designated as programmed cell death type II, and is characterized by the formation of autophagic vacuoles in the cytoplasm. Numerous herbs, including Chinese herbs, have been [...] Read more.

Accumulated evidence indicates that autophagy is a response of cancer cells to various anti-cancer therapies. Autophagy is designated as programmed cell death type II, and is characterized by the formation of autophagic vacuoles in the cytoplasm. Numerous herbs, including Chinese herbs, have been applied to cancer treatments as complementary and alternative medicines, supplements, or nutraceuticals to dampen the side or adverse effects of chemotherapy drugs. Moreover, the tumor suppressive actions of herbs and natural products induced autophagy that may lead to cell senescence, increase apoptosis-independent cell death or complement apoptotic processes. Hereby, the underlying mechanisms of natural autophagy inducers are cautiously reviewed in this article. Additionally, three natural compounds—curcumin, 16-hydroxycleroda-3,13-dien-15,16-olide, and prodigiosin—are presented as candidates for autophagy inducers that can trigger cell death in a supplement or alternative medicine for cancer therapy. Despite recent advancements in therapeutic drugs or agents of natural products in several cancers, it warrants further investigation in preclinical and clinical studies. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Autophagic Mechanism in Anti-Cancer Immunity: Its Pros and Cons for Cancer Therapy

by Ying-Ying Li, Lynn G. Feun, Angkana Thongkum, Chiao-Hui Tu, Shu-Mei Chen, Medhi Wangpaichitr, Chunjing Wu, Macus T. Kuo and Niramol Savaraj

Int. J. Mol. Sci. 2017, 18(6), 1297; https://doi.org/10.3390/ijms18061297 - 19 Jun 2017

Cited by 28 | Viewed by 7581

Abstract

Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, [...] Read more.

Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, and microenvironmental conditions. Currently, the majority of evidence support that autophagy in cancer cells is a vital mechanism bringing on resistance to current and prospective treatments, yet whether autophagy affects the anticancer immune response remains unclear and controversial. Accumulated studies have demonstrated that triggering autophagy is able to facilitate anticancer immunity due to an increase in immunogenicity, whereas other studies suggested that autophagy is likely to disarm anticancer immunity mediated by cytotoxic T cells and nature killer (NK) cells. Hence, this contradiction needs to be elucidated. In this review, we discuss the role of autophagy in cancer cells per se and in cancer microenvironment as well as its dual regulatory roles in immune surveillance through modulating presentation of tumor antigens, development of immune cells, and expression of immune checkpoints. We further focus on emerging roles of autophagy induced by current treatments and its impact on anticancer immune response, and illustrate the pros and cons of utilizing autophagy in cancer immunotherapy based on preclinical references. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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Open AccessReview

Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors

by Cynthia I. Chude and Ravi K. Amaravadi

Int. J. Mol. Sci. 2017, 18(6), 1279; https://doi.org/10.3390/ijms18061279 - 16 Jun 2017

Cited by 294 | Viewed by 12104

Abstract

Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer [...] Read more.

Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic. Full article

(This article belongs to the Special Issue Autophagy at the Intersection of the Immune System and Cancer)

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