Anticancer Activity of Diosgenin and its Semi-synthetic Derivatives: Role in Autophagy Mediated Cell Death and Induction of Apoptosis

2021 ◽  
Vol 21 ◽  
Author(s):  
Nivedita Bhardwaj ◽  
Nancy Tripathi ◽  
Bharat Goel ◽  
Shreyans K. Jain
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Anticancer Activity ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Rational Approach ◽  
Potential Candidate ◽  
Potential Implication ◽  
Apoptosis Protein ◽  
Synthetic Derivatives

: During cancer progression, the unrestricted proliferation of cells is supported by the impaired cell death response provoked by certain oncogenes. Both autophagy and apoptosis are the signaling pathways of cell death, which are targeted for cancer treatment. Defects in apoptosis result in reduced cell death and ultimately tumor progression. The tumor cells lacking apoptosis phenomena are killed by ROS- mediated autophagy. The autophagic programmed cell death requires apoptosis protein for inhibiting tumor growth; thus, the interconnection between these two pathways determines the fate of a cell. The cross-regulation of autophagy and apoptosis is an important aspect to modulate autophagy, apoptosis and to sensibilise apoptosis-resistant tumor cells under metabolic stress and might be a rational approach for drug designing strategy for the treatment of cancer. Numerous proteins involved in autophagy have been investigated as the druggable target for anticancer therapy. Several compounds of natural origin have been reported, to control autophagy activity through the PI3K/Akt/mTOR key pathway. Diosgenin, a steroidal sapogenin has emerged as a potential candidate for cancer treatment. It induces ROS-mediated autophagy, inhibits PI3K/Akt/mTOR pathway, and produces cytotoxicity selectively in cancer cells. This review aims to focus on optimal strategies using diosgenin to induce apoptosis by modulating the pathways involved in autophagy regulation and its potential implication in the treatment of various cancer. The discussion has been extended to the medicinal chemistry of semi-synthetic derivatives of diosgenin exhibiting anticancer activity.

scholarly journals Inducing death in tumor cells: roles of the inhibitor of apoptosis proteins

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 587 ◽  
Author(s):  
Darren Finlay ◽  
Peter Teriete ◽  
Mitchell Vamos ◽  
Nicholas D. P. Cosford ◽  
Kristiina Vuori
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Family Members ◽  
Cancer Therapeutics ◽  
Clinical State ◽  
Inhibitor Of Apoptosis ◽  
Current State ◽  
Apoptosis Protein

The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation but also from a lack of accompanying homeostatic cell death. Indeed, cancer cells regularly acquire resistance to programmed cell death, or apoptosis, which not only supports cancer progression but also leads to resistance to therapeutic agents. Thus, various approaches have been undertaken in order to induce apoptosis in tumor cells for therapeutic purposes. Here, we will focus our discussion on agents that directly affect the apoptotic machinery itself rather than on drugs that induce apoptosis in tumor cells indirectly, such as by DNA damage or kinase dependency inhibition. As the roles of the Bcl-2 family have been extensively studied and reviewed recently, we will focus in this review specifically on the inhibitor of apoptosis protein (IAP) family. IAPs are a disparate group of proteins that all contain a baculovirus IAP repeat domain, which is important for the inhibition of apoptosis in some, but not all, family members. We describe each of the family members with respect to their structural and functional similarities and differences and their respective roles in cancer. Finally, we also review the current state of IAPs as targets for anti-cancer therapeutics and discuss the current clinical state of IAP antagonists.

scholarly journals Elaborating the Role of Natural Products-Induced Autophagy in Cancer Treatment: Achievements and Artifacts in the State of the Art

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Ning Wang ◽  
Yibin Feng
Keyword(s):  
Cell Death ◽  
Natural Products ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Apoptotic Cell ◽  
Rapid Expansion ◽  
Drug Study

Autophagy is a homeostatic process that is highly conserved across different types of mammalian cells. Autophagy is able to relieve tumor cell from nutrient and oxidative stress during the rapid expansion of cancer. Excessive and sustained autophagy may lead to cell death and tumor shrinkage. It was shown in literature that many anticancer natural compounds and extracts could initiate autophagy in tumor cells. As summarized in this review, the tumor suppressive action of natural products-induced autophagy may lead to cell senescence, provoke apoptosis-independent cell death, and complement apoptotic cell death by robust or target-specific mechanisms. In some cases, natural products-induced autophagy could protect tumor cells from apoptotic death. Technical variations in detecting autophagy affect data quality, and study focus should be made on elaborating the role of autophagy in deciding cell fate. In vivo study monitoring of autophagy in cancer treatment is expected to be the future direction. The clinical-relevant action of autophagy-inducing natural products should be highlighted in future study. As natural products are an important resource in discovery of lead compound of anticancer drug, study on the role of autophagy in tumor suppressive effect of natural products continues to be necessary and emerging.

scholarly journals Conditionally Replicating Adenoviruses Kill Tumor Cells via a Basic Apoptotic Machinery-Independent Mechanism That Resembles Necrosis-Like Programmed Cell Death

2004 ◽  
Vol 78 (22) ◽  
pp. 12243-12251 ◽  
Author(s):  
Mohamed A. I. Abou El Hassan ◽  
Ida van der Meulen-Muileman ◽  
Saman Abbas ◽  
Frank A. E. Kruyt
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Anticancer Agents ◽  
Late Time ◽  
Apoptotic Pathway ◽  
P53 Expression ◽  
Apoptosis Protein ◽  
H460 Cells ◽  
E3 Region

ABSTRACT Conditionally replicating adenoviruses (CRAds) represent a promising class of novel anticancer agents that are used for virotherapy. The E1AΔ24 mutation-based viruses, Ad5-Δ24 [CRAd(E3−); E3 region deleted] and infectivity-enhanced Ad5-Δ24RGD [CRAd(E3+)] have been shown to potently eradicate tumor cells. The presence of the E3 region in the latter virus is known to improve cell killing that can be attributed to the presence of the oncolysis-enhancing Ad death protein. The more precise mechanism by which CRAds kill tumor cells is unclear, and the role of the host cell apoptotic machinery in this process has been addressed only in a limited way. Here, we examine the role of several major apoptotic pathways in the CRAd-induced killing of non-small-cell lung cancer H460 cells. As expected, CRAd(E3+) was more potent than CRAd(E3−). No evidence for the involvement of the p53-Bax apoptotic pathway was found. Western blot analyses demonstrated strong suppression of p53 expression and unchanged Bax levels during viral replication, and stable overexpression of human papillomavirus type 16-E6 in H460 cells did not affect killing by both CRAds. CRAd activity was also not hampered by stable overexpression of anti-apoptotic Bcl2 or BclXL, and endogenous Bcl2/BclXL protein levels remained constant during the oncolytic cycle. Some evidence for caspase processing was obtained at late time points after infection; however, the inhibition of caspases by the X-linked inhibitor of apoptosis protein overexpression or cotreatment with zVAD-fmk did not inhibit CRAd-dependent cell death. Analyses of several apoptotic features revealed no evidence for nuclear fragmentation or DNA laddering, although phosphatidylserine externalization was detected. We conclude that despite the known apoptosis-modulating abilities of individual Ad proteins, Ad5-Δ24-based CRAds trigger necrosis-like cell death. In addition, we propose that deregulated apoptosis in cancer cells, a possible drug resistance mechanism, provides no barrier for CRAd efficacy.

scholarly journals Tumor-Associated Macrophages: Combination of Therapies, the Approach to Improve Cancer Treatment

2021 ◽  
Vol 22 (13) ◽  
pp. 7239
Author(s):  
Pedram Moeini ◽  
Paulina Niedźwiedzka-Rystwej
Keyword(s):  
Immune System ◽  
Tumor Microenvironment ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Innate Immune System ◽  
Innate Immune ◽  
Tumor Associated Macrophages ◽  
Therapy Failure ◽  
Cellular Debris

Macrophages are one of the most important cells of the innate immune system and are known for their ability to engulf and digest foreign substances, including cellular debris and tumor cells. They can convert into tumor-associated macrophages (TAMs) when mature macrophages are recruited into the tumor microenvironment. Their role in cancer progression, metastasis, and therapy failure is of special note. The aim of this review is to understand how the presence of TAMs are both advantageous and disadvantageous in the immune system.

Research Progress in Flavonoids as Potential Anticancer Drug Including Synergy with Other Approaches

2020 ◽  
Vol 20 (20) ◽  
pp. 1791-1809 ◽  
Author(s):  
Yusuf Hussain ◽  
Suaib Luqman ◽  
Abha Meena
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cell Signalling ◽  
Resistance Mechanisms ◽  
Research Progress ◽  
Potential Candidate ◽  
Proliferating Cells ◽  
Oncology Research

Background: In chemotherapy for cancer, conventional drugs aim to target the rapidly growing and dividing cells at the early stages. However, at an advanced stage, cancer cells become less susceptible because of the multidrug resistance and the recruitment of alternative salvage pathways for their survival. Besides, owing to target non-selectivity, healthy proliferating cells also become vulnerable to the damage. The combination therapies offered using flavonoids to cure cancer not only exert an additive effect against cancer cells by targetting supplementary cell carnage pathways but also hampers the drug resistance mechanisms. Thus, the review aims to discuss the potential and pharmacokinetic limitations of flavonoids in cancer treatment. Further successful synergistic studies reported using flavonoids to treat cancer has been described along with potential drug delivery systems. Methods: A literature search was done by exploring various online databases like Pubmed, Scopus, and Google Scholar with the specific keywords like “Anticancer drugs”, “flavonoids”, “oncology research”, and “pharmacokinetics”. Results: Dietary phytochemicals, mainly flavonoids, hinder cell signalling responsible for multidrug resistance and cancer progression, primarily targeting cancer cells sparing normal cells. Such properties establish flavonoids as a potential candidate for synergistic therapy. However, due to low absorption and high metabolism rates, the bioavailability of flavonoids becomes a challenge. Such challenges may be overcome using novel approaches like derivatization, and single or co-delivery nano-complexes of flavonoids with conventional drugs. These new approaches may improve the pharmacokinetic and pharmacodynamic of flavonoids. Conclusion: This review highlights the application of flavonoids as a potential anticancer phytochemical class in combination with known anti-cancer drugs/nanoparticles. It also discusses flavonoid’s pharmacokinetics and pharmacodynamics issues and ways to overcome such issues. Moreover, it covers successful methodologies employed to establish flavonoids as a safe and effective phytochemical class for cancer treatment.

scholarly journals Minit-Livin Conjugated to Targeted Nanoparticles Inhibits Tumorigenicity

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4171-4171
Author(s):  
Ihab Abd Elrahman ◽  
Taher Nassar ◽  
Noha Khairi ◽  
Riki Perlman ◽  
Simon Benita ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
Luciferase Reporter ◽  
Gaussia Luciferase ◽  
Targeted Nanoparticles ◽  
Apoptosis Protein ◽  
Apoptotic Activity

Abstract We found that Livin, an Inhibitor of Apoptosis Protein, is specifically cleaved to produce a truncated Livin protein (tLivin) and demonstrated the paradoxical pro-apoptotic activity of tLivin. mini-tLivin (mtLivin) is a 70 aa derivative of tLivin that remarkably, exhibits a pro-apoptotic activity as potent as tLivin. Our findings regarding tLivin and mtLivin suggest unique therapeutic avenue against cancer. To improve the delivery and efficacy of mtLivin for treatment we conjugated mtLivin-to nanoparticles (NPs) of poly (lactide-co-glycolide) (PLGA) and targeted the nano-delivery system to diffuse large B-cell lymphoma (DLBCL) using CD40L. Delivery of mtLivin with nanoparticles should enhance stability, provide prolonged bioavailability, intracellular uptake and efficacy. We generated bifunctional mtLivin-CD40L-NPs to target mtLivin-NPs to DLBCL cells. Various cell lines were used to evaluate the biological activity of free and conjugated (targeted or not) mtLivin including 293T, 721.221 B cells, L428 Hodgkin's lymphoma, OCI-LY19 DLBCL cells and OCI-LY19- GLuc cells that constitutively express a gaussia luciferase reporter. Targeted, bifunctional mtLivin-CD40L-NPs elicited significant cell death of DLBCL cells while monofunctional mtLivin-NPs had a lower effect. mtLivin-NPs may induce cell death of some cell lines without targeting (e.g. 293T) yet targeting is required to induce marked cell death of DLBCL cells. To best mimic lymphoma disease in humans, a disseminated lymphoma model was used to evaluate the antitumor effect of targeted mtLivin treatment. NOD/SCID mice were injected with OCI-LY19- GLuc cells or into the tail vein. Gaussia luciferase reporter allows IVIS imaging to monitor tumor size and location in mice. Mice were treated approximately once a week with various mtLivin-NPs formulations. Luciferase signal was observed as early as day 2 after tumor cells injection. Immunohistochemistry for anti-CD20, a human B-cell marker, showed infiltration of OCI-ly19-Gluc cells in spleen and brain close to tumor cells injection (Day 2). With time, lymphoma infiltrations were detected in brain, bone marrow, lungs, spleen and liver. All control mice exhibited paralysis and did not survive beyond 28 days. In contrast, 37.5% of animals receiving mtLivin-NPs and 71.4 % of animals receiving mtLivin-CD40L-NPs achieved complete pathological tumor response and survived significantly longer. All treatments in this study were well-tolerated. In terms of mechanism, we show high caspase-3 activity in tumors from mice that were treated with mtLivin-CD40L-NPs demonstrating the ability of the nanoparticles to target the tumors and to induce apoptotic tumor cell death. The resistance of tumor cells to drug-induced apoptosis is a major cause of cancer treatment failure. We designed mtLitvin targeted nanoparticles constituting novel personalized therapeutic approach for resistant cancer. Disclosures No relevant conflicts of interest to declare.

scholarly journals Autophagy Regulation and Photodynamic Therapy: Insights to Improve Outcomes of Cancer Treatment

2021 ◽  
Vol 10 ◽  
Author(s):  
Waleska K. Martins ◽  
Renata Belotto ◽  
Maryana N. Silva ◽  
Daniel Grasso ◽  
Maynne D. Suriani ◽  
...  
Keyword(s):  
Cell Death ◽  
Photodynamic Therapy ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Light Sources ◽  
Regulated Cell Death ◽  
Age Related ◽  
Cell Death Mechanisms

Cancer is considered an age-related disease that, over the next 10 years, will become the most prevalent health problem worldwide. Although cancer therapy has remarkably improved in the last few decades, novel treatment concepts are needed to defeat this disease. Photodynamic Therapy (PDT) signalize a pathway to treat and manage several types of cancer. Over the past three decades, new light sources and photosensitizers (PS) have been developed to be applied in PDT. Nevertheless, there is a lack of knowledge to explain the main biochemical routes needed to trigger regulated cell death mechanisms, affecting, considerably, the scope of the PDT. Although autophagy modulation is being raised as an interesting strategy to be used in cancer therapy, the main aspects referring to the autophagy role over cell succumbing PDT-photoinduced damage remain elusive. Several reports emphasize cytoprotective autophagy, as an ultimate attempt of cells to cope with the photo-induced stress and to survive. Moreover, other underlying molecular mechanisms that evoke PDT-resistance of tumor cells were considered. We reviewed the paradigm about the PDT-regulated cell death mechanisms that involve autophagic impairment or boosted activation. To comprise the autophagy-targeted PDT-protocols to treat cancer, it was underlined those that alleviate or intensify PDT-resistance of tumor cells. Thereby, this review provides insights into the mechanisms by which PDT can be used to modulate autophagy and emphasizes how this field represents a promising therapeutic strategy for cancer treatment.

scholarly journals Molecular mechanism of cell ferroptosis and research progress in regulation of ferroptosis by noncoding RNAs in tumor cells

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Bumin Xie ◽  
Yuan Guo
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Tumor Cells ◽  
Molecular Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Noncoding Rnas ◽  
Research Progress ◽  
Circular Rnas ◽  
Regulated Cell Death

AbstractFerroptosis is a newly identified form of nonapoptotic regulated cell death characterized by iron-dependent accumulation of lipid reactive oxygen species. Morphologically and biochemically different from known types of cell death and apoptosis, ferroptosis promotes nervous system diseases, renal failure, ischemia–reperfusion injury, and the treatment of tumors. It could be induced by several mechanisms, including inhibition of glutathione peroxidase 4, lack of cysteine, and peroxidation of polyunsaturated fatty acids, but could be inhibited by iron chelators, lipophilic antioxidants, and some specific inhibitors. Ferroptosis is found to be closely related to the tumorigenesis, invasion, and metastasis of tumors. Noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), microRNAs, and circular RNAs, do not encode proteins. NcRNAs are found to be capable of regulating the molecular mechanism of ferroptosis in tumor cells post transcription. Ferroptosis provides a new method for cancer treatment. Although several studies have confirmed the important role of ferroptosis in cancer treatment, its specific affecting mechanism is unclear. Here we reviewed the molecular mechanism of ferroptosis in tumor cells and the relationship between ferroptosis and the three important ncRNAs.

Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Chen ◽  
PH Wang ◽  
SS Chen ◽  
CC Wen ◽  
YH Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cell ◽  
Tumor Cells ◽  
Cancer Vaccine ◽  
Immunogenic Cell Death

Optical Properties of Photodynamic Therapy Drugs in Different Environments: The Paradigmatic Case of Temoporfin

2020 ◽  
Author(s):  
busenur Aslanoglu ◽  
Ilya Yakavets ◽  
Vladimir Zorin ◽  
Henri-Pierre Lassalle ◽  
Francesca Ingrosso ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Optical Properties ◽  
Photodynamic Therapy ◽  
Minimally Invasive ◽  
Visible Light ◽  
Cancer Treatment ◽  
Singlet Oxygen ◽  
Tumor Cells ◽  
Molecular Oxygen ◽  
Computational Tools

Computational tools have been used to study the photophysical and photochemical features of photosensitizers in photodynamic therapy (PDT) –a minimally invasive, less aggressive alternative for cancer treatment. PDT is mainly based by the activation of molecular oxygen through the action of a photoexcited sensitizer (photosensitizer). Temoporfin, widely known as mTHPC, is a second-generation photosensitizer, which produces the cytotoxic singlet oxygen when irradiated with visible light and hence destroys tumor cells. However, the bioavailability of the mostly hydrophobic photosensitizer, and hence its incorporation into the cells, is fundamental to achieve the desired effect on malignant tissues by PDT. In this study, we focus on the optical properties of the temoporfin chromophore in different environments –in <i>vacuo</i>, in solution, encapsulated in drug delivery agents, namely cyclodextrin, and interacting with a lipid bilayer.

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