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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 78-85

Delineating the role of autophagy in driving the resistance to cancer chemotherapy

1 Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati, Assam, India
2 DBT Centre for Molecular Biology and Cancer Research, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
3 Department of Head and Neck Surgery, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India

Date of Submission01-Nov-2021
Date of Decision08-Nov-2021
Date of Acceptance09-Nov-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Dr. V G M. Naidu
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, SilaKatamur, Halugurisuk P O-Changsari, Kamrup, Guwahati – 781 101, Assam
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aort.aort_26_21

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The development of resistance is one of the major complications faced by an oncologist for cancer treatment. Autophagy plays a crucial role in driving this resistance against most antineoplastic therapies. The evolutionarily conserved autophagy process meant for quality control of cellular organelles and protein complexes is overwhelmed by proliferative signals from various carcinogens. This leads to the accumulation of defective oncogenic proteins leading to carcinogenesis. As the tumor proliferates and grows in size, it reboots its autophagy pathways to supplement its ever-growing need for nutrients, oxygen, and energy supply. This review will discuss various molecular mechanisms of how physiological and metabolic stressors modulate autophagy, which drives the cancer cell's journey from dormancy to survival by fuelling the metabolic pathways involving internal cell restructuring and reshaping the tumor microenvironment. Considering the preclinical success of autophagy modulators for cancer treatment, this review will bring a new perspective and mechanistic explanation for using autophagy inhibitors for curtailing tumor progression and later using autophagy inducers for preventing cancer remission. This review will also help to formulate or repurpose safer and effective stand-alone and combination anticancer treatment strategies involving autophagy modulators.

Keywords: Autophagy, cancer, chemotherapy, treatment

How to cite this article:
Shantanu P A, Syamprasad N P, Rajdev B, Gawali B, Rai AK, Rahman T, M. Naidu V G. Delineating the role of autophagy in driving the resistance to cancer chemotherapy. Ann Oncol Res Ther 2021;1:78-85

How to cite this URL:
Shantanu P A, Syamprasad N P, Rajdev B, Gawali B, Rai AK, Rahman T, M. Naidu V G. Delineating the role of autophagy in driving the resistance to cancer chemotherapy. Ann Oncol Res Ther [serial online] 2021 [cited 2022 Aug 8];1:78-85. Available from: http://www.aort.com/text.asp?2021/1/2/78/333309

  Introduction Top

Cancer: An ever-evolving problem with limited therapies

More than a century of oncology research has failed to develop a treatment that can treat all forms of cancer. This has been overshadowed by identifying multiple targets and factors involved in oncogenesis and cancer progression.[1] Recent studies show that more than 19 million population suffer from one or another form of cancer, out of which 9.5 million die every year.[2] This is due to the emergence of drug resistance in most cases. Emergence resistance to cancer chemotherapy is a well-observed phenomenon where the dose of the anticancer drug has to be escalated beyond the maximum tolerated dose to treat cancer.[3] The current cancer treatment mainly involves surgery, cytotoxic drugs, radiation, endocrine therapy, and immune therapy.[1],[3],[4],[5] Despite achievements made in treating cancers, the emergence of resistance continues to be significant cancer chemotherapy-induced complications. Cancer resistance arises from multiple factors such as genetic and epigenetic alterations promoting drug efflux and alteration to cell signaling and metabolic pathways.[3] Macroautophagy (autophagy) is one of the major metabolic alternations adopted by the cancer cells to evade chemotherapy- and radiotherapy-induced apoptosis.[6]

Autophagy: A cellular salvage pathway for energy

Autophagy is a cellular salvage pathway in which cancer cells catabolize their cellular organelles for energy to aid survival and adaptation. As cancer proliferates and grows in size, multiple factors such as reactive oxygen species (ROS), limited nutrient availability, and hypoxia induce autophagy. The autophagic process is triggered by the metabolic stress mammalian target for rapamycin (mTOR) sensor, which dynamically responds to environmental signals. In nutrient abundance, mTOR is activated and binds to the ULK complex, thereby inhibiting the complex in the process. However, when the metabolic stress nucleation process is triggered, mTOR is deactivated and dissociates from the ULK complex, allowing it to phosphorylate focal adhesion family interacting protein 200 kDa mAtg13 initiating autophagy. Following initiation, activated ULK complex recruits beclin 1, human vacuolar protein sorting associated protein 34, Atg14 L, and p150 initiates double membrane phagophore formation, followed by elongation of synthesized phagophore by Atg 12 and 5 is catalyzed by Atg 10 and 7. This elongated structure is known as autophagosomes. As autophagosome matures, it incorporates LC3-I and LC3-II, completing the autophagosome formation. The P62/ sequestosome 1 (SQSTM1) which is embedded during autophagosome formation complexes with LC3, identifies various ubiquitylated, damaged protein aggregates, and cell organelles delivering them to autophagosomes for digestion. Mature autophagosome containing engulfed cargos now fuses with lysosomes to form autolysosomes. The engulfed proteins organelles are exposed to lysosomal hydrolases that digest and release nutrients and energy in the process. Following lysosomal digestion, autolysosomes undergo a recycling process called autolysosomal reformation, recovering lysosomes, and autophagosomes, thereby maintaining cellular hemostasis.[6],[7]

For many years, there was a controversy regarding whether promoting autophagy beneficial for cancer. This review will discuss how unregulated autophagy-induced apoptosis might be beneficial and responsible for early-stage cancer regression. However, in later stages, factors such as ROS, hypoxia, and even cancer chemotherapeutic drugs such as doxorubicin, cisplatin, 5-fluorouracil (through ROS), PI3K inhibitors, and tyrosine kinase inhibitors inadvertently induce resistance by triggering autophagy-induced pathways, thereby aggravating cancer [Figure 1].[8],[9],[10],[11],[12]
Figure 1: Chemotherapy and reactive oxygen species triggering autophagy. When a cell is in a proliferative state through continuous stimulation of growth factors, the requisite PIP3 level keeps the autophagy process in check by triggering mammalian target for rapamycin-mediated suppression of autophagy. Once the metabolic stress is induced through lack of hypoxia, nutrients, reactive oxygen species, or PI3K inhibitors, mammalian target for rapamycin-mediated autophagy suppression is abrogated, leading to cannibalizing its cellular organelles and protein complexes for energy. This induces resistance in cancer cells. Further inhibiting alone autophagy does not lead to cell death as proliferative mechanisms aids cell proliferation. Various autophagy inhibitors have been identified, such as 3-methyl alanine, chloroquine, and hydroxychloroquine. However, their preclinical success was not replicated in clinical trials. These drugs failed to achieve complete autophagy inhibition. Thus, drugs targeting both proliferative and adaptive pathways are required for the effective treatment of cancer

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Inducers and regulators of autophagy

The tumor microenvironment encompasses extreme stress conditions caused by ROS, hypoxia, inflammation, nutrient deprivation, and loss of stimulation from insulin and growth factors that induce autophagy.[13]

Nutrient deprivation leading to autophagy

There are two well-characterized pathways responsible for sensing the nutrient PI3K-AMPK-mTOR-mediated glucose and Ras-cAMP-PKB-mediated pathway in mammalians, negatively regulating autophagy[14] [Figure 2].
Figure 2: Autophagy mediates both internal and external restructuring for maintaining a higher proliferative state. Nutrient deprivation and reactive oxygen species stimulate autophagy which degrades KEAP-1, the protein responsible for degrading nuclear factor erythroid 2-related factor 2. This facilitates nuclear factor erythroid 2-related factor 2 nuclear translocation and upregulates antioxidants enzymes responsible for scavenging reactive oxygen species. The upregulated autophagy also contributes to the downregulation of death receptors and MHCs; further, the sustained levels of autophagy in tumor-associated macrophages release immunotolerance molecules (e.g., IDOs, CTLA-4, PDL-1s). These processes aid cancer cells in escaping immunosurveillance. The higher levels of autophagy also mediate epithelial–mesenchymal transition and angiogenesis to reroute the supply of nutrients and metastasis

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PI3K-AMPK-mammalian target for rapamycin-mediated regulation of autophagy

All the pathways converging at mTOR will, in turn, regulate autophagy-mediated cellular adaptation (such as PI3K, GPCR, cAMP, RTK, and Wnt-GSK3B). As discussed above, mTOR binds to the ULK complex inhibiting the initiation of autophagy. The activity of mTOR is governed by the cellular metabolic sensor AMP-activated protein kinase (AMPK). Adenosine monophosphate/ adenosine triphosphate (AMP/ATP) and adenosine diphosphate / adenosine triphosphate (ADP/ATP) levels are sensed by AMPK kinase when ATP is not actively synthesized by glycolysis and the citric acid cycle. The accumulation of AMPs leads to activation of AMPK by binding to the γ-subunit of AMPK, inhibiting the dephosphorylation of α T172, resulting in increased activation of AMPK. Similarly, when a cell is in a proliferative state, the activity of AMPK can be regulated by phosphorylation at the α-T172 site by calcium calmodulin kinases or mitogen-activated protein kinases (MAPKs), thus reducing the activity of AMPK. This characteristic energy-sensing activity of AMPK is crucial for any cells to avoid apoptosis due to reduced ATP levels by triggering autophagy to compensate for lack of nutrients.[14]

AMPK regulates autophagy on multiple levels by inhibiting mTOR and activating ULK and various components of the beclin-1-VPS34 complex. Thus, initiating autophagy by promoting nucleation.[14]

Receptors responsible for sensing of availability of nutrients' extracellular micro-environment such as G protein-coupled receptor, class C, group 6, member A (GPRC6A), γ-aminobutyric acid B receptor 1 (GABBR1), calcium-sensing receptor, heterodimeric taste receptors, and various metabotropic glutamate receptors, all of which sense one or more amino acids;[2] free fatty acid receptor 1 (FFAR1), and FFAR4, etc., regulate autophagy by increasing cAMP, inositol triphosphate, and diacylglycerol levels.[14]

Acetyl-CoA-mediated autophagy regulation

Acetyl-CoA is regarded as the common end product for glycolysis, beta-oxidation, and amino-acid metabolism. The reduction of acetyl-CoA levels leads to deacetylation of some proteins such as Atg5, Atg7, Atg8, and Atg12, leading to activation of autophagy through AMPK and mTOR pathway. In a study done by Mariño et al., 2014 showed that depletion of acetyl CoA levels following starvation can be corelated with activation of autophagy in cell lines and mice models.[15] Treatment pharmacological agents such as histone deacetylation inhibitors also lead to autophagy activation. This stimulation of autophagy may be due to reduced acetyl-CoA acts as a substrate for acetyltransferases which plays a crucial role in fatty acid metabolism, glycolysis, citric acid, and mitochondrial respiration. Specific mutations of Kirsten rat sarcoma (KRAS) promote acetyl-CoA synthesis by upregulating phosphorylation of ATP citrate lyase. This results in inhibition of autophagy and increased aggressiveness of cancer due to constitutive activation of Akt. When KRAS mutant cancers are treated with PI3K inhibitors, they develop resistance by switching on previously inhibited autophagy mechanisms.[16]

Stress as a trigger for autophagy

Various extracellular and intracellular stress factors play a vital role in triggering autophagy as a coping mechanism. Recent studies have provided an insight into the molecular mechanism behind various stress-induced autophagy.

Reactive oxygen species-induced autophagy

Nutrient deprivation, oxidative stress due to chemotherapy, and mitochondrial and endoplasmic stress are primary generators of ROS which drive autophagy. The ROS produced oxidizes DNA, lipids, and proteins rendering them defective, which drives autophagy. Mitochondria is the primary source of oxidative stress inside a cell. The relatively stable intermediate H2O2 produced in response to oxidative stress diffuses through mitochondrial membrane accelerates conversion of LCI to LCII through thiol modification of ATG4. The H2O2 produced also activates AMPK, which, in turn, inhibits mTOR, activating autophagy. Another mechanism through which ROS enforces autophagy is by increasing Ca2+ mediated signaling through calcium/calmodulin-dependent protein kinase and AMPK activation, resulting in an increase in autophagy gene expression and increased autophagy activation.[16]

Oxidative stress also mediated autophagy through inducing nuclear factor erythroid 2-related factor 2 (Nrf2) translocation, which enforces positive feedback for autophagy gene expression, thereby degrading Kelch-like ECH-associated protein 1 (KEAP-1) (the protein responsible for Nrf2 inhibition) in p62 dependant manner. Nutrient deprivation/hypoxia triggers p53 which inhibits tumor protein 53-induced glycolysis and apoptosis regulator (TIGAR). This leads to upregulation of damage-regulated autophagy modulator, sestrin 1, sestrin 2, increased activation of AMPK, and inhibition of mTORC1[14],[17],[18] [Figure 2].

Endoplasmic reticulum stress-induced autophagy

Endoplasmic reticular is a vital cell organelle involved in protein synthesis, folding, and initiating pathways responsible for vesicular movement and serving as a calcium reservoir. Hypoxia, expression of pro-aggregatory proteins, nutrient deprivation, and oxidative stress accumulate misfolded proteins and cause Ca2+ efflux from endoplasmic reticulum (ER). This leads to an overwhelming ER folding capacity. This is due to reduced disulfide formation and glycosylation, activating inositol-requiring kinase 1 (IRE1)-PERK-HSP70-mediated autophagy.[16]

Hypoxia-induced autophagy through beclin-1

The lower oxygen levels due to un-inhibited cellular proliferations lead to hypoxia aggravation, elevating oxidative stress and mitochondrial autophagy. The excess mitochondria are removed from the cell by the autophagy process called mitophagy. Mitophagy enhances the expression of HIF-1, which, in turn, induces BNIP3 (BCL2 adenovirus E1-19 kDa interacting protein; a proapoptotic BCl2 family member protein) expression. BNIP3 competes with beclin-1 for a binding site with BCL2. This releases beclin-1 for induction of autophagy.[14],[16],[19]

Autophagy: Dormancy to restructuring for cancer cell survival

Autophagy driving epithelial–mesenchymal transitions

Epithelial–mesenchymal transition (EMT) is controlled mainly by three major pathways PI3K-Akt-AMPK, Wnt, NF-kB, and transforming growth factor (TGF)-B. These cellular signalings are involved with mitochondria and cytoskeletal restructuring – the functional interaction of autophagy to the essential cell organelles like mitochondria and cytoskeleton links to the EMT process. There is a stage-dependent relationship of autophagy with the EMT process; normal cells in the abundance of nutrients and growth factors activate the proliferative signaling such as PI3K-Akt-AMPK pathway switching off autophagy and EMT process through inhibiting mTOR, N-cadherins, and upregulating E-cadherins. However, when a cell becomes cancerous due to increased mass, the autophagy activated through the TGF-β pathway provides the necessary nutrients for driving the EMT process.[20],[21]

The activation of the PI3K-Akt pathway results in the activation of S6 ribosomal proteins, upregulating adhesion proteins' expression and forming double-membrane structures inhibiting both EMT and autophagy. However, prolonged PI3K activity promotes malignant transformation, cell migration, and extracellular degradation matrix by inhibiting autophagy and enhancing EMT. This is due to upregulating SNAIL, SLUG, integrin-linked kinase, and WNT/B-catenin signaling. The Wnt pathway activation by PI3K is due to phosphorylation of β-catenin and GSK3 β by phosphorylation. β-catenin combines with E-cadherin to promote EMT.[21]

As tumor mass increases, the cancer cells and stromal fibroblast secrete TGFβ into the tumor microenvironment and act as the primary driver of EMT through SNAIL, Smad2, Smad3, and Wnt signaling cascade. TGFβ also considerably enhances autophagy gene expression, AMPK, PKA, and CREB activation, promoting autophagy and EMT.[21]

Autophagy driving vascular remodeling in the tumor microenvironment

Endothelial cells form the inner lining of all the vascular and subvascular compartments and are curial for maintaining a continuous supply of blood, nutrients, hormones, and other blood and lymph-borne factors to tissues. The integrity and plasticity of vascular compartments rely heavily on the behavior of endothelial cells. Hypoxia, ROS, acidity induced by shear stress, and pathological insults are considered as the primary drivers of vascular plasticity. These factors induce endothelial cell proliferation leading to sprouting vascular compartments to hypoxic nutrients deprived tissue locations. This restores the continuous supply of oxygen and nutrient supply, thereby reversing the hypoxic conditions. Once the nutrient supply is established, the newly formed vascular structure matures to form established capillaries. It is this feature of inducing vascular sprouting induced by endothelial cells under hypoxic and nutrient deprived condition that cancer cell cells exploit to reroute nutrient and oxygen supply to itself. The continuous proliferation of cancer cells makes the tumor microenvironment nutrient deprived, induces hypoxia, and increases acidity due to switching over to anaerobic respiration. Normally, endothelial cells revert to a quiescent state once nutrient and oxygen supply is restored. However, tumor-induced angiogenesis is fuelled by a continuous imbalance between pro-anti-angiogenic factors driven by the vascular endothelial growth factor-VEGR2 axis, autophagy-induced decrease in CDH5 expression, inactivation of NOTCH signaling, and immune system. The newly formed vessels remain highly proliferative, permeable with variable diameters and low structural stability, making is liable for collapse. This exacerbates hypoxia, acidity, and nutrient scarcity, increasing the imbalance between pro- and anti-angiogenic factors.[22]

Modulation of autophagy for taming host immunological response against cancer

Autophagy is one of the critical pathways modulating the responses of NK cells, dendritic cells, macrophages, B cells, and T cells as it controls its cellular activation, proliferation, adaptation, and cell death.[23] At the same time, autophagy also controls the release of the both pro and anti-inflammatory cytokines, which in-turn mediates the immune cells autophagic functions like TGF B, interferon Y, interleukin (IL 1), IL 2, and IL 12 induce autophagy, visa viz IL 4, IL 10, IL 13 are autophagy inhibitors.[23],[24] Conventional therapies such as radiotherapy and chemotherapy are used to treat cancer work by inducing uncontrolled autophagy (due to damaged DNA and ROS), leading to autophagic cell death.[3],[25],[26] Even the success of immunotherapy, the latest anticancer treatment, relies heavily on cancer and immune cell's autophagic status.[26]

Autophagy enhances the presentation of antigens to antigen-presenting cells and CD8+ cytotoxic T cells and propels the ability of the innate immune system to recognize and eliminate potentially cancerous cells. Conversely, autophagy also weakens the host's immune response due to immunotherapy. This impedes the clinical development of autophagy activators and inhibitors.[26]

The responses due to innate immunity are mediated by autophagic stimulation by toll-like receptors (TLRs) and nucleotide oligomerization (NOD)-domain-like receptors, which induce autophagy by REK and JNK pathways. TLR7 induces autophagy by engaging ATG8 and beclin-1 to myeloid differentiation factor 88 (MYD88) to clear inflammasomes and activate inflammatory signaling cascades via NF-kB and MAP kinase activation. This results in a release of both pro-inflammatory and anti-inflammatory cytokines. By altering the balance between pro- and anti-inflammatory cytokines, this NOD-mediated immunomodulation plays a critical role initiation of cancer. The role of NOD1-CARD4 (caspase recruitment domain) and NOD2/CARD15 receptors in the precipitation of lung cancer is being explored in the Turkish population.[26]

Activation of autophagy by mTOR enhances CD8+ T cells to differentiate into CTLs; however, autophagy inhibition by mTOR phosphorylation promotes its differentiation into Th cells. Autophagy also drives dendritic, plasma, and B cell development, differentiation antigen-specific immunoglobulin G; and immunoglobulin M production by enhancing antigen presentation. The association of FOXO1 and ATG7 initiates NKT recruitment and effector actions against the tumor. ULK1 and JNK activation-triggered autophagy are essential for macrophage production at different stages. The inhibition of macrophages autophagy promotes M1-like tumor-associated-macrophages (TAMs) polarization resulting in increased specific immune responses; however, autophagy triggered by binding of IL6 and CCL2 to IL6R and CCR2, respectively, enhances macrophages polarization to the immunosuppressive M2-like TAMs. The inhibition of p38 MAPK or mTORC1 can block the development of neutrophils via inducing autophagy. In addition, autophagy can facilitate myeloid-derived suppressor cell growth. Tregs, M2-like TAMs, and myeloid-derived suppressor cells promote tumor development.[26]

The recent less than anticipated antitumor response of immunotherapeutic strategies in clinical trials can be attributed to immunotolerance induced by indoleamine 2,3 dioxygenase (IDO), CTLA-4, and PD-1. These immunogenic tolerance molecules induce tolerance through autophagy pathways. Indoleamine 2,3 dioxygenase is secreted by tumor cells, tumor-associated MDSC, and TAMs. Indoleamine 2,3 dioxygenase induces autophagy by inhibiting tryptophan sufficiency signals and stimulating general control nonderepressible 2, blocking S6K and inhibiting mTOR, and this leads to autophagy. Similarly, PDL-1/PD-1 signaling inhibitors (or sigma1 modulators) and CLTA4 inhibitors also trigger autophagy-induced resistance by inhibiting nutrient sufficiency signals. Many clinical trials have begun to understand this concept, exploring the possibility of using autophagic inhibitors such as chloroquine and hydroxychloroquine with PDL-1 inhibitors[26] [Table 1] and [Table 2].
Table 1: Summary of significant clinical trial results of chloroquine/hydroxychloroquine in treatment of various malignancies

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Table 2: Currently ongoing some important clinical trials with chloroquine or hydroxychloroquine administration in anticancer therapy

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Future scope

The ability of cancer cells to switch on and off a particular metabolic pathway makes it harder to formulate a cancer treatment strategy. Autophagy is one such adaptation cancer that switches off at the initial stages of cancer and progressively switches on to overcome adverse conditions associated with cancer progression and anticancer treatment.[37] The basal autophagy levels in cancer cells are elevated than that of normal cells counterpart. As tumor mass progresses in size, cancer cells' reliance on autophagy is intensified due to its multifaceted role in restructuring cells' internal and external microenvironment to rerouting nutrients. Many conventional and latest anticancer therapies (acting through DNA damage, PI3K-mTOR inhibitors, and tyrosine kinase inhibitors) intensify cell autophagy addiction, thereby inadvertently inducing resistance.[1],[4],[8],[19],[37],[38] The drug tissue bioavailability issues, patient compliance, and other compatibilities associated with cancer patients accelerate resistance induction. Various metabolic stressors such as ROS induce autophagy (DNA damage and mitochondrial and ER stress), glucose deprivation, hypoxia, and fall in ATP/AMP ratio, which predominantly relies on switching on autophagy with mTOR, AMPK, and Bcl2-beclin-1 pathway or elevating ATG genes.[14],[17] This initiates double-membrane formation and incorporation of LC3A, which then matures to LC3B, then p62-SQSTSM binds to LC3B, which then sequesters ubiquitylated molecules such as mitochondria and protein complexes such as KEAP-1 and Smad3. Once proteins are complexed, a double-membrane structure is completing to form autophagosomes. Then, lysosomes fuse with autophagosomes to form autolysosomes, and digest entrapped organelles and protein complexes. The nutrients are released, which drives cell survival and restructuring pathways.[39] The KEAP-1 sequestered is an inhibitory protein of Nrf2, the lack of KEAP-1 results in enhancing cancer cell's antioxidant defense mechanism by upregulating antioxidant enzymes.[17]

The TGF-β released from enhanced autophagy in tumor cells and tumor-associated macrophages drives EMT changes.[20],[21] Autophagy also decreases the expression of CD5 and cathepsin D associated with degradation of sequestered proteins also is upregulated and degrades the extracellular matrix.[21] This accelerates angiogenesis and rerouting of oxygen and blood supply. The newly formed vessels remain fragile with variable diameters. This makes them susceptible to collapse, exacerbating hypoxic conditions.[22] The role of autophagy in inducing tumor tolerance cannot be ignored. The increase of TGF-β and immunotolerance molecules (such as IDO, CTLA-4, and PDL-1) released by tumor and TAMs induces tolerance through autophagy.[26] Thus, inhibition of autophagy becomes one of the prime objectives in curtailing tumor growth.

However, the ability of autophagy to remove defective organelles and proteins and induce apoptosis cannot be ignored. The lack to autophagy or defective autophagic process can also be attributed to oncogenesis. Thus, this fact advocates the use of autophagic inhibitors to curtail tumor progression and development of resistance and autophagic induces to prevent cancer remission by removing defective oncogenic proteins.[37] The autophagic inducers could also potentiate antigen-presentation of various oncogenic proteins, thus enhancing immunosurveillance and antitumor immunity. Inhibition of alone autophagy or proliferative pathways (like PI3K pathway) tends to be cytostatic in nature due to interlinked nature of these two pathways. One pathway compensates for the loss of signaling from another, this promotes resistance. This is the reason why both autophagic inhibitors and PI3K molecules perform well in preclinical studies but fail in clinical trials. There is a need to develop more potent autophagy inhibitors and combinations inhibiting both proliferative and autophagy pathways for the successful treatment of cancers. Once cancer treatment is over, autophagy inducers can be used for maintaining a complete cancer remission state. Thus, understanding the autophagic status of the cancer through biopsies and other means, could help in formulation and development of safer and effective anticancer treatment strategies and drug combinations.[40]


The author wants to express their thanks to the Director, NIPER, Guwahati, for providing facilities necessary facilities and inflrastrure.

Financial support and sponsorship

This work is supported by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, Natioanl Institute of Pharmaceutical Education and Research (NIPER) Guwahati, India. Department of Biotechnology, DBT-North East Twinning Project (BT/PR25319/NER/95/1133/2017), and National Mission for Himalayan studies, Ministry of Environment, Forest, and Climate Change, Government of India, for the fellowship provided to authors (GBPI/NMHS/2017 − 18/HSF-02).

Conflicts of interest

There are no conflicts of interest.

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