Publications by authors named "Gautam Sethi"

356 Publications

Extracellular vesicles, the cornerstone of next-generation cancer diagnosis?

Semin Cancer Biol 2021 May 11. Epub 2021 May 11.

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Cancer has risen up to be a major cause of mortality worldwide over the past decades. Despite advancements in cancer screening and diagnostics, a significant number of cancers are still diagnosed at a late stage with poor prognosis. Hence, the discovery of reliable and accurate methods to diagnose cancer early would be of great help in reducing cancer mortality. Extracellular vesicles (EVs) are phospholipid vesicles found in many biofluids and are released by almost all types of cells. In recent years, using EVs as cancer biomarkers has garnered attention as a novel technique of cancer diagnosis. Compared with traditional tissue biopsy, there are many advantages that this novel diagnostic tool presents - it is less invasive, detects early-stage asymptomatic cancers, and allows for monitoring of tumour progression. As such, EV biomarkers have great potential in improving the diagnostic accuracy of cancers and guiding subsequent therapeutic decisions. Efficient isolation and accurate characterization of EVs are essential for reliable outcomes of clinical application. However, these are complicated by the size and biomolecular diversity of EVs. In this review, we present an analysis and evaluation of the current techniques of EV isolation and characterization, as well as discuss the potential EV biomarkers for specific types of cancer. Taken together, EV biomarkers have a lot of potential as a novel method in cancer diagnostics and diagnosis. However, more work is still needed to streamline the purification, characterization and biomarker identification process to ensure optimal outcomes for patients.
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http://dx.doi.org/10.1016/j.semcancer.2021.05.011DOI Listing
May 2021

Nigella Plants - Traditional Uses, Bioactive Phytoconstituents, Preclinical and Clinical Studies.

Front Pharmacol 2021 26;12:625386. Epub 2021 Apr 26.

Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

is a small genus of the family Ranunculaceae, which includes some popular species due to their culinary and medicinal properties, especially in Eastern Europe, Middle East, Western, and Central Asia. Therefore, this review covers the traditional uses and phytochemical composition of and, in particular, . The pharmacological studies reported , and in humans have also been reviewed. One of the main strength of the use of is that the seeds are rich in the omega-6 fatty acid linoleic acid and provide an extra-source of dietary phytochemicals, including the bioactive thymoquinone, and characteristics saponins, alkaloids, and flavonoids. Among species, . L. is the most studied plant from the genus. Due to the phytochemical composition and pharmacological properties, the seed and seed oil from this plant can be considered as good candidates to formulate functional ingredients on the basis of folklore and scientific knowledge. Nonetheless, the main limations are that more studies, especially, clinical trials are required to standardize the results, e.g. to establish active molecules, dosage, chemical profile, long-term effects and impact of cooking/incorporation into foods.
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http://dx.doi.org/10.3389/fphar.2021.625386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107825PMC
April 2021

Bacteria as a treasure house of secondary metabolites with anticancer potential.

Semin Cancer Biol 2021 May 9. Epub 2021 May 9.

Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, 570006, India. Electronic address:

Cancer stands in the frontline among leading killers worldwide and the annual mortality rate is expected to reach 16.4 million by 2040. Humans suffer from about 200 different types of cancers and many of them have a small number of approved therapeutic agents. Moreover, several types of major cancers are diagnosed at advanced stages as a result of which the existing therapies have limited efficacy against them and contribute to a dismal prognosis. Therefore, it is essential to develop novel potent anticancer agents to counteract cancer-driven lethality. Natural sources such as bacteria, plants, fungi, and marine microorganisms have been serving as an inexhaustible source of anticancer agents. Notably, over 13,000 natural compounds endowed with different pharmacological properties have been isolated from different bacterial sources. In the present article, we have discussed about the importance of natural products, with special emphasis on bacterial metabolites for cancer therapy. Subsequently, we have comprehensively discussed the various sources, mechanisms of action, toxicity issues, and off-target effects of clinically used anticancer drugs (such as actinomycin D, bleomycin, carfilzomib, doxorubicin, ixabepilone, mitomycin C, pentostatin, rapalogs, and romidepsin) that have been derived from different bacteria. Furthermore, we have also discussed some of the major secondary metabolites that are currently in the clinical trials or which have demonstrated potent anticancer activity in preclinical models. Besides, we have elaborated on the application of metagenomics in drug discovery and briefly described about anticancer agents identified through the metagenomics approach.
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http://dx.doi.org/10.1016/j.semcancer.2021.05.006DOI Listing
May 2021

Role of histone acetyltransferase inhibitors in cancer therapy.

Adv Protein Chem Struct Biol 2021 2;125:149-191. Epub 2020 Oct 2.

Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea. Electronic address:

The development of cancer is a complex phenomenon driven by various extrinsic as well as intrinsic risk factors including epigenetic modifications. These post-translational modifications are encountered in diverse cancer cells and appear for a relatively short span of time. These changes can significantly affect various oncogenic genes and proteins involved in cancer initiation and progression. Histone lysine acetylation and deacetylation processes are controlled by two opposing classes of enzymes that modulate gene regulation either by adding an acetyl moiety on a histone lysine residue by histone lysine acetyltransferases (KATs) or via removing it by histone deacetylases (KDACs). Deregulated KAT activity has been implicated in the development of several diseases including cancer and can be targeted for the development of anti-neoplastic drugs. Here, we describe the predominant epigenetic changes that can affect key KAT superfamily members during carcinogenesis and briefly highlight the pharmacological potential of employing lysine acetyltransferase inhibitors (KATi) for cancer therapy.
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http://dx.doi.org/10.1016/bs.apcsb.2020.08.002DOI Listing
October 2020

Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis.

Cancers (Basel) 2021 Apr 14;13(8). Epub 2021 Apr 14.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.

In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells-highlight some future perspectives in cancer therapy by targeting cytoskeleton.
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http://dx.doi.org/10.3390/cancers13081882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070945PMC
April 2021

Regulation of Nuclear Factor-KappaB (NF-κB) signaling pathway by non-coding RNAs in cancer: Inhibiting or promoting carcinogenesis?

Cancer Lett 2021 Jul 7;509:63-80. Epub 2021 Apr 7.

NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore. Electronic address:

The nuclear factor-kappaB (NF-κB) signaling pathway is considered as a potential therapeutic target in cancer therapy. It has been well established that transcription factor NF-κB is involved in regulating physiological and pathological events including inflammation, immune response and differentiation. Increasing evidences suggest that deregulated NF-κB signaling can enhance cancer cell proliferation, metastasis and also mediate radio-as well as chemo-resistance. On the contrary, non-coding RNAs (ncRNAs) have been found to modulate NF-κB signaling pathway under different settings. MicroRNAs (miRNAs) can dually inhibit/induce NF-κB signaling thereby affecting the growth and migration of cancer cells. Furthermore, the response of cancer cells to radiotherapy and chemotherapy may also be regulated by miRNAs. Regulation of NF-κB by miRNAs may be mediated via binding to 3-UTR region. Interestingly, anti-tumor compounds can increase the expression of tumor-suppressor miRNAs in inhibiting NF-κB activation and the progression of cancers. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) can also effectively modulate NF-κB signaling thus affecting tumorigenesis. It is noteworthy that several studies have demonstrated that lncRNAs and circRNAs can affect miRNAs in targeting NF-κB activation. They can act as competing endogenous RNA (ceRNA) thereby reducing miRNA expression to induce NF-κB activation that can in turn promote cancer progression and malignancy.
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http://dx.doi.org/10.1016/j.canlet.2021.03.025DOI Listing
July 2021

A Novel Role of Bergamottin in Attenuating Cancer Associated Cachexia by Diverse Molecular Mechanisms.

Cancers (Basel) 2021 Mar 17;13(6). Epub 2021 Mar 17.

Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.

Purpose: The potential effects of bergamotiin (BGM) on the suppression of cancer cachexia was evaluated under in vitro and in vivo conditions to investigate its possible inhibitory effects on the muscle and fat loss.

Method: The differentiated C2C12 and 3T3L1 cells were treated with BGM after the induction of cancer-cachexia with pancreatic cancer conditioned media (CM). The expression levels of the various molecules involved in the differentiation and loss of muscle and fat (MuRF-1, Atrogin-1, C/EBPα, and PPARγ) were analyzed by Western blot and oil red O staining. For in vivo experiment, MIA PaCa-2 cells were injected into the mice ( = 6), and then BGM (1 mg/kg) was intraperitoneally administered to analyze muscle and adipose tissue by Hematoxylin and Eosin staining and Western blot.

Result: BGM displayed a significant effect on the inhibition of muscle and fat catabolism under both in vitro and in vivo conditions. The results of the in vivo experiment revealed a remarkable suppressive effect of BGM on the weight loss in mice.

Conclusions: The potential effects of BGM on the inhibition of muscle and fat catabolism in vitro and in vivo were thus confirmed. Based on the results, the impact of BGM on cancer cachexia could be possibly analyzed in the future clinical studies.
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http://dx.doi.org/10.3390/cancers13061347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002497PMC
March 2021

New approaches in extracellular vesicle engineering for improving the efficacy of anti-cancer therapies.

Semin Cancer Biol 2021 Feb 17. Epub 2021 Feb 17.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute for Digital Medicine, Immunology Programme and Cancer Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; N.1 Institute for Health, National University of Singapore, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Cancer is a disease that evolves continuously with unpredictable outcomes. Although conventional chemotherapy can display significant antitumor effects, the lack of specificity and poor bioavailability remain major concerns in cancer therapy. Moreover, with the advent of novel anti-cancer gene therapies, there is an urgent need for drug delivery vectors capable of bypassing cellular barriers and efficiently transferring therapeutic cargo to recipient cells. A number of drug delivery systems have been proposed to overcome these limitations, but their successful clinical translation has been hampered by the onset of unexpected side effects and associated toxicities. The application of extracellular vesicles (EVs), a class of naturally released, cell-derived particles, as drug delivery vectors presents a breakthrough in nanomedicine, taking into account their biocompatibility and natural role in intercellular communication. Combining the advantageous intrinsic properties of EVs with surface functionalization and the encapsulation of drugs allows for a new class of engineered EVs that serve as effective therapeutic carriers. Here, we describe the various successful approaches involving the application of engineered EVs as bio-derived drug delivery vectors in cancer therapy. The latest and most effective strategies of engineering EVs to improve drug loading, stealth properties and tumour targeting capabilities of EVs are debated. Finally, current obstacles and future perspectives of smart engineered EVs are discussed.
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http://dx.doi.org/10.1016/j.semcancer.2021.02.010DOI Listing
February 2021

Featuring the special issue guest editor.

Cancer Lett 2021 May 18;505:73-74. Epub 2021 Feb 18.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore. Electronic address:

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http://dx.doi.org/10.1016/j.canlet.2021.01.033DOI Listing
May 2021

Plasma osteopontin as a biomarker of Alzheimer's disease and vascular cognitive impairment.

Sci Rep 2021 Feb 17;11(1):4010. Epub 2021 Feb 17.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Singapore, 117599, Singapore.

Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer's disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.
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http://dx.doi.org/10.1038/s41598-021-83601-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889621PMC
February 2021

Deguelin targets multiple oncogenic signaling pathways to combat human malignancies.

Pharmacol Res 2021 Apr 11;166:105487. Epub 2021 Feb 11.

Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA. Electronic address:

Cancer is an anomalous growth and differentiation of cells known to be governed by oncogenic factors. Plant-based natural metabolites have been well recognized to possess chemopreventive properties. Deguelin, a natural rotenoid, is among the class of bioactive phytoconstituents from a diverse range of plants with potential antineoplastic effects in different cancer subtypes. However, the precise mechanisms of how deguelin inhibits tumor progression remains elusive. Deguelin has shown promising results in targeting the hallmarks of tumor progression via inducing tumor apoptosis, cell cycle arrest, and inhibition of angiogenesis and metastasis. Based on initial scientific excerpts, deguelin has been reported to inhibit tumor growth via different signaling pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, serine/threonine protein kinase B (also known as Akt), mammalian target of rapamycin, nuclear factor-κB, matrix metalloproteinase (MMP)-2, MMP-9 and caspase-3, caspase-8, and caspase-9. This review summarizes the mechanistic insights of antineoplastic action of deguelin to gain a clear understanding of its therapeutic effects in cancer. The anticancer potential of deguelin with respect to its efficacy in targeting tumorigenesis via nanotechnological approaches is also investigated. The initial scientific findings have presented deguelin as a promising antitumorigenic agent which can be used for monotherapy as well as synergistically to augment efficacy of chemotherapeutic treatment regimes.
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http://dx.doi.org/10.1016/j.phrs.2021.105487DOI Listing
April 2021

Pomegranate bioactive constituents target multiple oncogenic and oncosuppressive signaling for cancer prevention and intervention.

Semin Cancer Biol 2021 Jan 24. Epub 2021 Jan 24.

Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA. Electronic address:

Cancer remains to be the second highest cause of mortality in our society, falling just short of heart disease. Despite major advancement in cancer therapy over the past decade, momentum has been gaining for an alternative approach of using naturally-occurring and dietary agents for cancer prevention and management. Research on pomegranate (Punica granatum L.), a fruit of the Punicaceae family, has shown enormous potential for cancer prevention and intervention. In addition to a rich source of polyphenols, including flavonoids and ellagitannins, in its juice, pomegranate also houses hundreds of other phytochemicals in its pericarp, seed, flower, bark, flowers and leaves. These phytochemicals provide powerful antiproliferative, anti-inflammatory, antioxidant, anti-invasive, antimigratory, anti-angiogenic and anti-metastatic effects without significant toxicity. This makes the use of its various extracts a very attractive strategy to our current battle against cancer. This review article presents a systematic, comprehensive and critical review of research on pomegranate-derived products in both cancer prevention and intervention. It discusses the chemical constituents of pomegranate, the results of both preclinical (in vitro, ex vivo and in vivo) and clinical studies on the anticancer effect of pomegranate phytochemicals and molecular targets in numerous types of cancers, such as breast, gastrointestinal tract (oral, colon, liver and pancreas), gynecological (uterine and ovarian), hematological (lymphoma, leukemia and myeloma), lung, neurological (glioma), urogenital (bladder and prostate), bioavailability, pharmacokinetics and safety of pomegranate constituents. In order to guide the direction of future research, we have also included current limitations and challenges in the field and our post analysis recommendation.
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http://dx.doi.org/10.1016/j.semcancer.2021.01.006DOI Listing
January 2021

Putting the BRK on breast cancer: From molecular target to therapeutics.

Theranostics 2021 1;11(3):1115-1128. Epub 2021 Jan 1.

Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

BReast tumor Kinase (BRK, also known as PTK6) is a non-receptor tyrosine kinase that is highly expressed in breast carcinomas while having low expression in the normal mammary gland, which hints at the oncogenic nature of this kinase in breast cancer. In the past twenty-six years since the discovery of BRK, an increasing number of studies have strived to understand the cellular roles of BRK in breast cancer. Since then, BRK has been found both and to activate a multitude of oncoproteins to promote cell proliferation, metastasis, and cancer development. The compelling evidence concerning the oncogenic roles of BRK has also led, since then, to the rapid and exponential development of inhibitors against BRK. This review highlights recent advances in BRK biology in contributing to the "hallmarks of cancer", as well as BRK's therapeutic significance. Importantly, this review consolidates all known inhibitors of BRK activity and highlights the connection between drug action and BRK-mediated effects. Despite the volume of inhibitors designed against BRK, none have progressed into clinical phase. Understanding the successes and challenges of these inhibitor developments are crucial for the future improvements of new inhibitors that can be clinically relevant.
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http://dx.doi.org/10.7150/thno.49716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738883PMC
January 2021

LDL cholesterol promotes the proliferation of prostate and pancreatic cancer cells by activating the STAT3 pathway.

J Cell Physiol 2021 Jul 23;236(7):5253-5264. Epub 2020 Dec 23.

Department of Science in Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.

Hypercholesterolemia has been found to be closely linked with a significant increase in both cancer incidence and mortality. However, the exact correlation between serum cholesterol levels and cancer has not been completely deciphered. Here we analyzed the effect of low-density lipoprotein (LDL) cholesterol on prostate and pancreatic cancer cells. We noted that LDL induced a substantial STAT3 activation and JAK1, JAK2, Src activation in diverse prostate and pancreatic tumor cells. Moreover, LDL promoted cancer cell proliferation, migration, and invasion as well as upregulated the expression of diverse oncogenic gene products. However, deletion of LDL-activated STAT3 in LNCaP and PANC-1 cells and reduced LDL-induced cell viability. Simvastatin (SV) treatment also alleviated LDL-induced cell viability and migration ability in both the prostate and pancreatic tumor cells. These results demonstrate that LDL-induced STAT3 activation may exert a profound effect on the proliferation and survival of tumor cells.
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http://dx.doi.org/10.1002/jcp.30229DOI Listing
July 2021

The pleiotropic role of transcription factor STAT3 in oncogenesis and its targeting through natural products for cancer prevention and therapy.

Med Res Rev 2020 Dec 1. Epub 2020 Dec 1.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Signal transducer and activator of transcription 3 (STAT3) is one of the crucial transcription factors, responsible for regulating cellular proliferation, cellular differentiation, migration, programmed cell death, inflammatory response, angiogenesis, and immune activation. In this review, we have discussed the classical regulation of STAT3 via diverse growth factors, cytokines, G-protein-coupled receptors, as well as toll-like receptors. We have also highlighted the potential role of noncoding RNAs in regulating STAT3 signaling. However, the deregulation of STAT3 signaling has been found to be associated with the initiation and progression of both solid and hematological malignancies. Additionally, hyperactivation of STAT3 signaling can maintain the cancer stem cell phenotype by modulating the tumor microenvironment, cellular metabolism, and immune responses to favor drug resistance and metastasis. Finally, we have also discussed several plausible ways to target oncogenic STAT3 signaling using various small molecules derived from natural products.
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http://dx.doi.org/10.1002/med.21761DOI Listing
December 2020

Targeting Hypoxia-Inducible Factor-1-Mediated Metastasis for Cancer Therapy.

Antioxid Redox Signal 2021 Jan 25. Epub 2021 Jan 25.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Hypoxia is emerging as a crucial regulator of the tumor microenvironment; it governs the metastatic potential of multiple primary cancers. It is also potentially involved in the regulation of tumorigenesis, tumor metabolism, and proangiogenic activity. A wealth of clinical data across a wide range of cancer types has revealed strong correlations between hypoxia or the overexpression of hypoxia-inducible transcription factors and the rates of distant metastases and poor prognoses. Hypoxia-inducible factor (HIF)-1α, one of the key regulatory molecules of the HIF-1 signaling pathways, is involved in multiple crucial steps in the metastatic cascade. Here, we present recent findings on the roles of the HIF-1 complex in tumor metastasis and highlight the potential of HIF-1α as a target for abrogating tumor metastasis. Moreover, we systematically describe the regulatory role of HIF-1 at each step of the metastatic cascade. Finally, we present the most recent advances in potential pharmacological interventions and the development of specific HIF-1 inhibitors for blocking tumor metastasis. Well-designed clinical trials are urgently needed to validate the anti-metastatic activity of HIF-1 inhibitors discovered in preclinical models.
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http://dx.doi.org/10.1089/ars.2019.7935DOI Listing
January 2021

Designing precision medicine panels for drug refractory cancers targeting cancer stemness traits.

Biochim Biophys Acta Rev Cancer 2021 01 11;1875(1):188475. Epub 2020 Nov 11.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore.

Cancer is one amongst the major causes of death today and cancer biology is one of the most well researched fields in medicine. The driving force behind cancer is considered to be a minor subpopulation of cells, the cancer stem cells (CSCs). Similar to other stem cells, these cells are self-renewing and proliferating but CSCs are also difficult to target by chemo- or radio-therapies. Cancer stem cells are known to be present in most of the cancer subgroups such as carcinoma, sarcoma, myeloma, leukemia, lymphomas and mixed cancer types. There is a wide gamut of factors attributed to the stemness of cancers, ranging from dysregulated signaling pathways, and activation of enzymes aiding immune evasion, to conducive tumor microenvironment, to name a few. The defining outcome of the increased presence of CSCs is tumor metastasis and relapse. Predictive medicine approach based on the plethora of CSC markers would be a move towards precision medicine to specifically identify CSC-rich tumors. In this review, we discuss the cancer subtypes and the role of different CSC specific markers in these varying subtypes. We also categorize the CSC markers based their defining trait contributing to stemness. This review thus provides a comprehensive approach to catalogue a predictive set of markers to identify the resistant and refractory cancer stem cell population within different tumor subtypes, so as to facilitate better prognosis and targeted therapeutic strategies.
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http://dx.doi.org/10.1016/j.bbcan.2020.188475DOI Listing
January 2021

Lauric acid ameliorates lipopolysaccharide (LPS)-induced liver inflammation by mediating TLR4/MyD88 pathway in Sprague Dawley (SD) rats.

Life Sci 2021 Jan 11;265:118750. Epub 2020 Nov 11.

School of Biosciences, Faculty of Science, The University of Melbourne, Victoria 3010, Australia; Department of Pharmacology and Therapeutics, School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia; Department of Pharmacology and Therapeutics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address:

Background: Lipopolysaccharide (LPS) is an endotoxin that leads to inflammation in many organs, including liver. It binds to pattern recognition receptors, that generally recognise pathogen expressed molecules to transduce signals that result in a multifaceted network of intracellular responses ending up in inflammation. Aim In this study, we used lauric acid (LA), a constituent abundantly found in coconut oil to determine its anti-inflammatory role in LPS-induced liver inflammation in Sprague Dawley (SD) rats.

Method: Male SD rats were divided into five groups (n = 8), injected with LPS and thereafter treated with LA (50 and 100 mg/kg) or vehicle orally for 14 days. After fourteen days of LA treatment, all the groups were humanely killed to investigate biochemical parameters followed by pro-inflammatory cytokine markers; tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β. Moreover, liver tissues were harvested for histopathological studies and evaluation of targeted protein expression with western blot and localisation through immunohistochemistry (IHC).

Results: The study results showed that treatment of LA 50 and 100 mg/kg for 14 days were able to reduce the elevated level of pro-inflammatory cytokines, liver inflammation, and downregulated the expression of TLR4/NF-κB mediating proteins in liver tissues.

Conclusion: These findings suggest that treatment of LA has a protective role against LPS-induced liver inflammation in rats, thus, warrants further in-depth investigation through mechanistic approaches in different study models.
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http://dx.doi.org/10.1016/j.lfs.2020.118750DOI Listing
January 2021

Suppression of the USP10/CCND1 axis induces glioblastoma cell apoptosis.

Acta Pharmacol Sin 2020 Nov 12. Epub 2020 Nov 12.

Department of Pharmacology, Soochow University, Suzhou, 215123, China.

Recent studies show that the expression of CCND1, a key factor in cell cycle control, is increased following the progress and deteriotation of glioma and predicts poor outcomes. On the other hand, dysregulated deubiquitinase USP10 also predicts poor prognosis for patients with glioblastoma (GBM). In the present study, we investigated the interplay between CCND1 protein and USP10 in GBM cells. We showed that the expression of CCND1 was significantly higher in both GBM tissues and GBM-derived stem cells. USP10 interacted with CCND1 and prevented its K48- but not K63-linked polyubiquitination in GBM U251 and HS683 cells, which led to increased CCND1 stability. Consistent with the action of USP10 on CCND1, knockdown of USP10 by single-guided RNA downregulated CCND1 and caused GBM cell cycle arrest at the G1 phase and induced GBM cell apoptosis. To implement this finding in the treatment of GBMs, we screened a natural product library and found that acevaltrate (AVT), an active component derived from the herbal plant Valeriana jatamansi Jones was strikingly potent to induce GBM cell apoptosis, which was confirmed by the Annexin V staining and activation of the apoptotic signals. Furthermore, we revealed that AVT concentration-dependently suppressed USP10-mediated deubiquitination on CCND1 therefore inducing CCND1 protein degradation. Collectively, the present study demonstrates that the USP10/CCND1 axis could be a promising therapeutic target for patients with GBMs.
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http://dx.doi.org/10.1038/s41401-020-00551-xDOI Listing
November 2020

Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma.

J Adv Res 2020 Nov 13;26:83-94. Epub 2020 Jul 13.

Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Introduction: Epithelial-mesenchymal transition (EMT) is a process of transdifferentiation where epithelial cells attain mesenchymal phenotype to gain invasive properties and thus, can contribute to metastasis of tumor cells.

Objectives: The antimetastatic and antitumor efficacy of brusatol (BT) was investigated in a hepatocellular carcinoma (HCC) model.

Methods: We evaluated the action of BT on EMT process using various biological assays in HCC cell lines and its effect on tumorigenesis in an orthotopic mouse model.

Results: We found that BT treatment restored the expression of Occludin, E-cadherin (epithelial markers) while suppressing the levels of different mesenchymal markers in HCC cells and tumor tissues. Moreover, we observed a decline in the expression of transcription factors (Snail, Twist). Since the expression of these two factors can be regulated by STAT3 signaling, we deciphered the influence of BT on modulation of this pathway. BT suppressed the phosphorylation of STAT3 and STAT3 depletion using siRNA resulted in the restoration of epithelial markers. Importantly, BT (1mg/kg) reduced the tumor burden in orthotopic mouse model with a concurrent decline in lung metastasis.

Conclusions: Overall, our results demonstrate that BT interferes with STAT3 induced metastasis by altering the expression of EMT-related proteins in HCC model.
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http://dx.doi.org/10.1016/j.jare.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584682PMC
November 2020

Pharmacological significance of the non-canonical NF-κB pathway in tumorigenesis.

Biochim Biophys Acta Rev Cancer 2020 12 12;1874(2):188449. Epub 2020 Oct 12.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore. Electronic address:

The understanding of the impact of the non-canonical NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway in several human diseases including autoimmune, inflammatory and cancers has been on the rise. This pathway induces the expression of several important genes involved in diverse biological processes. Though progress has been made in understanding the activation, regulation and biological functions of the non-canonical NF-κB signaling mechanism, no specific drug has been approved to target NF-κB inducing kinase (NIK), the key signaling molecule in this pathway. The inhibition of NIK can serve as a potential therapeutic strategy for various ailments, especially for the treatment of different types of human cancers. There are other targetable downstream molecules in this pathway as well. This review highlights the possible role of the non-canonical NF-κB pathway in normal physiology as well as in different cancers and discusses about various pharmacological strategies to modulate the activation of this pathway.
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http://dx.doi.org/10.1016/j.bbcan.2020.188449DOI Listing
December 2020

Corilagin Represses Epithelial to Mesenchymal Transition Process Through Modulating Wnt/β-Catenin Signaling Cascade.

Biomolecules 2020 10 5;10(10). Epub 2020 Oct 5.

Department of Science in Korean Medicine, Kyung Hee University, Seoul 02447, Korea.

Corilagin (CLG), a major component of several medicinal plants, can exhibit diverse pharmacological properties including those of anti-cancer, anti-inflammatory, and hepatoprotective qualities. However, there are no prior studies on its potential impact on the epithelial-to-mesenchymal transition (EMT) process. EMT can lead to dissemination of tumor cells into other organs and promote cancer progression. Hence, we aimed to investigate the effect of CLG on EMT and its mechanism(s) of action in tumor cells. We noted that CLG reduced the expression of various epithelial markers and up-regulated the expression of Occludin and E-cadherin in both basal and TGFβ-stimulated tumor cells. CLG treatment also abrogated cellular invasion and migration in colon and prostate carcinoma cells. In addition, CLG effectively attenuated the Wnt/β-catenin signaling cascade in TGFβ-stimulated cells. Overall, our study suggests that CLG may function as and effective modulator of EMT and metastasis in neoplastic cells.
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http://dx.doi.org/10.3390/biom10101406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600105PMC
October 2020

The implication of long non-coding RNAs in the diagnosis, pathogenesis and drug resistance of pancreatic ductal adenocarcinoma and their possible therapeutic potential.

Biochim Biophys Acta Rev Cancer 2020 12 29;1874(2):188423. Epub 2020 Aug 29.

Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh 201313, India. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is one of the lethal malignancies with the lowest median and overall survival rate among all human malignancies. The major problems with the PDAC are the late diagnosis, metastasis, and acquired resistance to chemotherapeutic agents in the clinic. Over the last decade, the long non-coding RNAs (lncRNAs) have been discovered and occupies a significantly large proportion of the human genome. Recent studies have proved that lncRNAs can play a crucial role in the majority of key cellular processes involved in the maintenance of cellular homeostasis by regulating various molecular mechanisms. The deregulation of lncRNAs has been associated with various chronic diseases including human malignancies. Several lncRNAs have tumor-specific expression making them an ideal and excellent target for designing the novel therapeutic strategies against human malignancies. We have discussed how lncRNA expression can be used for the diagnosis and prognosis of PDAC. The current review discusses the potential role and molecular mechanism of lncRNA in regulating the prominent hallmarks of cancer including abnormal growth, survival, metastasis, and drug-resistance in PDAC. Importantly, we also highlight the possible application of various therapeutic strategies including small interfering RNA, CRISPR-Cas9, antisense oligonucleotides, locked nucleic acid Gapmers, small molecules, aptamers, lncRNA promoter to target the lncRNA as a novel and viable options for treatment of PDAC.
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http://dx.doi.org/10.1016/j.bbcan.2020.188423DOI Listing
December 2020

Bioactive compounds from marine invertebrates as potent anticancer drugs: the possible pharmacophores modulating cell death pathways.

Mol Biol Rep 2020 Sep 14;47(9):7209-7228. Epub 2020 Aug 14.

Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, 769008, India.

Marine invertebrates are extremely diverse, largely productive, untapped oceanic resources with chemically unique bioactive lead compound contributing a wide range of screening for the discovery of anticancer compounds. The lead compounds have unfurled an extensive array of pharmacological properties owing to the presence of polyphenols, alkaloids, terpenoids and other secondary metabolites. The antioxidant, immunomodulatory and anti-tumor activities exhibited, are possibly regulated by the apoptosis induction, scavenging of ROS and modulation of cellular signaling pathways to defy the cellular deafness during carcinogenesis. Despite the enriched bioactive compounds, the marine invertebrates are largely unexplored as identification, screening, pre-clinical and clinical assessment of lead compounds and their synthetic analogs remain a major task to be solved. In the current review, we focus on the principle strategy and underlying mechanisms deployed by the bioactive anticancer compounds derived from marine invertebrates to combat cancer with special insight into the cell death mechanism.
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http://dx.doi.org/10.1007/s11033-020-05709-8DOI Listing
September 2020

Role of microRNA/Epithelial-to-Mesenchymal Transition Axis in the Metastasis of Bladder Cancer.

Biomolecules 2020 08 7;10(8). Epub 2020 Aug 7.

Sabanci University Nanotechnology Research and Application Center (SUNUM), Sabanci University, Tuzla, Istanbul 34956, Turkey.

Bladder cancer (BC) is the 11th most common diagnosed cancer, and a number of factors including environmental and genetic ones participate in BC development. Metastasis of BC cells into neighboring and distant tissues significantly reduces overall survival of patients with this life-threatening disorder. Recently, studies have focused on revealing molecular pathways involved in metastasis of BC cells, and in this review, we focus on microRNAs (miRNAs) and their regulatory effect on epithelial-to-mesenchymal transition (EMT) mechanisms that can regulate metastasis. EMT is a vital process for migration of BC cells, and inhibition of this mechanism restricts invasion of BC cells. MiRNAs are endogenous non-coding RNAs with 19-24 nucleotides capable of regulating different cellular events, and EMT is one of them. In BC cells, miRNAs are able to both induce and/or inhibit EMT. For regulation of EMT, miRNAs affect different molecular pathways such as transforming growth factor-beta (TGF-β), Snail, Slug, ZEB1/2, CD44, NSBP1, which are, discussed in detail this review. Besides, miRNA/EMT axis can also be regulated by upstream mediators such as lncRNAs, circRNAs and targeted by diverse anti-tumor agents. These topics are also discussed here to reveal diverse molecular pathways involved in migration of BC cells and strategies to target them to develop effective therapeutics.
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http://dx.doi.org/10.3390/biom10081159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464913PMC
August 2020

A comprehensive review of genetic alterations and molecular targeted therapies for the implementation of personalized medicine in acute myeloid leukemia.

J Mol Med (Berl) 2020 08 3;98(8):1069-1091. Epub 2020 Jul 3.

Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, 201313, India.

Acute myeloid leukemia (AML) is an extremely heterogeneous disease defined by the clonal growth of myeloblasts/promyelocytes not only in the bone marrow but also in peripheral blood and/or tissues. Gene mutations and chromosomal abnormalities are usually associated with aberrant proliferation and/or block in the normal differentiation of hematopoietic cells. So far, the combination of cytogenetic profiling and molecular and gene mutation analyses remains an essential tool for the classification, diagnosis, prognosis, and treatment for AML. This review gives an overview on how the development of novel innovative technologies has allowed us not only to detect the genetic alterations as early as possible but also to understand the molecular pathogenesis of AML to develop novel targeted therapies. We also discuss the remarkable advances made during the last decade to understand the AML genome both at primary and relapse diseases and how genetic alterations might influence the distinct biological groups as well as the clonal evolution of disease during the diagnosis and relapse. Also, the review focuses on how the persistence of epigenetic gene mutations during morphological remission is associated with relapse. It is suggested that along with the prognostic and therapeutic mutations, the novel molecular targeted therapies either approved by FDA or those under clinical trials including CART-cell therapy would be of immense importance in the effective management of AML.
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http://dx.doi.org/10.1007/s00109-020-01944-5DOI Listing
August 2020

Mechanistic Involvement of Long Non-Coding RNAs in Oncotherapeutics Resistance in Triple-Negative Breast Cancer.

Cells 2020 06 21;9(6). Epub 2020 Jun 21.

Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India.

Triple-negative breast cancer (TNBC) is one of the most lethal forms of breast cancer (BC), with a significant disease burden worldwide. Chemoresistance and lack of targeted therapeutics are major hindrances to effective treatments in the clinic and are crucial causes of a worse prognosis and high rate of relapse/recurrence in patients diagnosed with TNBC. In the last decade, long non-coding RNAs (lncRNAs) have been found to perform a pivotal role in most cellular functions. The aberrant functional expression of lncRNAs plays an ever-increasing role in the progression of diverse malignancies, including TNBC. Therefore, lncRNAs have been recently studied as predictors and modifiers of chemoresistance. Our review discusses the potential involvement of lncRNAs in drug-resistant mechanisms commonly found in TNBC and highlights various therapeutic strategies to target lncRNAs in this malignancy.
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http://dx.doi.org/10.3390/cells9061511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349003PMC
June 2020

Mango ( L.): a magnificent plant with cancer preventive and anticancer therapeutic potential.

Crit Rev Food Sci Nutr 2020 Jun 8:1-27. Epub 2020 Jun 8.

Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA.

L. (mango), a long-living evergreen plant belonging to the Anacardiaceae family, has been cultivated for thousands of years in the Indian subcontinent for its excellent fruits which represent a rich source of fiber, vitamin A and C, essential amino acids, and a plethora of phytochemicals. is extensively used in various traditional systems of medicine to prevent and treat several diseases. The health-promoting and disease-preventing effects of are attributed to a number of bioactive phytochemicals, including polyphenols, terpenoids, carotenoid and phytosterols, found in the leaf, bark, edible flesh, peel, and seed. has been shown to exhibit various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, antidiabetic, antiobesity, and anticancer effects. There are a few studies conducted that have indicated the nontoxic nature of mango constituents. However, while there are numerous individual studies investigating anticancer effects of various constituents from the mango tree, an up-to-date, comprehensive and critical review of available research data has not been performed according to our knowledge. The purpose of this review is to present a comprehensive and critical evaluation of cancer preventive and anticancer therapeutic potential of and its phytochemicals with special focus on the cellular and molecular mechanisms of action. The bioavailability, pharmacokinetics, and safety profile of individual phytocomponents of as well as current limitations, challenges, and future directions of research have also been discussed.
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http://dx.doi.org/10.1080/10408398.2020.1771678DOI Listing
June 2020

Association of the Epithelial-Mesenchymal Transition (EMT) with Cisplatin Resistance.

Int J Mol Sci 2020 Jun 3;21(11). Epub 2020 Jun 3.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.

Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial-mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell-cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.
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http://dx.doi.org/10.3390/ijms21114002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312011PMC
June 2020

Autophagy-modulating phytochemicals in cancer therapeutics: Current evidences and future perspectives.

Semin Cancer Biol 2020 May 22. Epub 2020 May 22.

Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India. Electronic address:

Autophagy is an intracellular catabolic self-cannibalism that eliminates dysfunctional cytoplasmic cargos by the fusion of cargo-containing autophagosomes with lysosomes to maintain cyto-homeostasis. Autophagy sustains a dynamic interlink between cytoprotective and cytostatic function during malignant transformation in a context-dependent manner. The antioxidant and immunomodulatory phyto-products govern autophagy and autophagy-associated signaling pathways to combat cellular incompetence during malignant transformation. Moreover, in a close cellular signaling circuit, autophagy regulates aberrant epigenetic modulation and inflammation, which limits tumor metastasis. Thus, manipulating autophagy for induction of cell death and associated regulatory phenomena will embark on a new strategy for tumor suppression with wide therapeutic implications. Despite the prodigious availability of lead pharmacophores in nature, the central autophagy regulating entities, their explicit target, as well as pre-clinical and clinical assessment remains a major question to be answered. In addition to this, the stage-specific regulation of autophagy and mode of action with natural products in regulating the key autophagic molecules, control of tumor-specific pathways in relation to modulation of autophagic network specify therapeutic target in caner. Moreover, the molecular pathway specificity and enhanced efficacy of the pre-existing chemotherapeutic agents in co-treatment with these phytochemicals hold high prevalence for target specific cancer therapeutics. Hence, the multi-specific role of phytochemicals in a cellular and tumor context dependent manner raises immense curiosity for investigating of novel therapeutic avenues. In this perspective, this review discusses about diverse implicit mechanisms deployed by the bioactive compounds in diagnosis and therapeutics approach during cancer progression with special insight into autophagic regulation.
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http://dx.doi.org/10.1016/j.semcancer.2020.05.008DOI Listing
May 2020