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1.
Molecular mechanisms of anticancer activities of polyphyllin VII.
Ahmad, B, Rehman, SU, Azizullah, A, Khan, MF, Din, SRU, Ahmad, M, Ali, A, Tahir, N, Azam, N, Gamallat, Y, et al
Chemical biology & drug design. 2021;(4):914-929
Abstract
Cancer is the leading cause of mortality in the world. The major therapies for cancer treatment are chemotherapy, surgery, and radiation therapy. All these therapies expensive, toxic and show resistance. The plant-derived compounds are considered safe, cost-effective and target cancer through different pathways. In these pathways include oxidative stress, mitochondrial dependent and independent, STAT3, NF-kB, MAPKs, cell cycle, and autophagy pathways. One of the new plants derived compounds is Polyphyllin VII (PPVII), which target cancer through different molecular mechanisms. In literature, there is a review gap of studies on PPVII; therefore in the current review, we summarized the available studies on PPVII to provide a base for future research.
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2.
The Most Competent Plant-Derived Natural Products for Targeting Apoptosis in Cancer Therapy.
Rajabi, S, Maresca, M, Yumashev, AV, Choopani, R, Hajimehdipoor, H
Biomolecules. 2021;(4)
Abstract
Cancer is a challenging problem for the global health community, and its increasing burden necessitates seeking novel and alternative therapies. Most cancers share six basic characteristics known as "cancer hallmarks", including uncontrolled proliferation, refractoriness to proliferation blockers, escaping apoptosis, unlimited proliferation, enhanced angiogenesis, and metastatic spread. Apoptosis, as one of the best-known programmed cell death processes, is generally promoted through two signaling pathways, including the intrinsic and extrinsic cascades. These pathways comprise several components that their alterations can render an apoptosis-resistance phenotype to the cell. Therefore, targeting more than one molecule in apoptotic pathways can be a novel and efficient approach for both identifying new anticancer therapeutics and preventing resistance to therapy. The main purpose of this review is to summarize data showing that various plant extracts and plant-derived molecules can activate both intrinsic and extrinsic apoptosis pathways in human cancer cells, making them attractive candidates in cancer treatment.
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3.
Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma.
Innao, V, Rizzo, V, Allegra, AG, Musolino, C, Allegra, A
Cells. 2021;(2)
Abstract
Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs' efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.
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4.
Heme Oxgenase-1, a Cardinal Modulator of Regulated Cell Death and Inflammation.
Ryter, SW
Cells. 2021;(3)
Abstract
Heme oxygenase catalyzes the rate-limiting step in heme degradation in order to generate biliverdin, carbon monoxide (CO), and iron. The inducible form of the enzyme, heme oxygenase-1 (HO-1), exerts a central role in cellular protection. The substrate, heme, is a potent pro-oxidant that can accelerate inflammatory injury and promote cell death. HO-1 has been implicated as a key mediator of inflammatory cell and tissue injury, as validated in preclinical models of acute lung injury and sepsis. A large body of work has also implicated HO-1 as a cytoprotective molecule against various forms of cell death, including necrosis, apoptosis and newly recognized regulated cell death (RCD) programs such as necroptosis, pyroptosis, and ferroptosis. While the antiapoptotic potential of HO-1 and its reaction product CO in apoptosis regulation has been extensively characterized, relatively fewer studies have explored the regulatory role of HO-1 in other forms of necrotic and inflammatory RCD (i.e., pyroptosis, necroptosis and ferroptosis). HO-1 may provide anti-inflammatory protection in necroptosis or pyroptosis. In contrast, in ferroptosis, HO-1 may play a pro-death role via enhancing iron release. HO-1 has also been implicated in co-regulation of autophagy, a cellular homeostatic program for catabolic recycling of proteins and organelles. While autophagy is primarily associated with cell survival, its occurrence can coincide with RCD programs. This review will summarize the roles of HO-1 and its reaction products in co-regulating RCD and autophagy programs, with its implication for both protective and detrimental tissue responses, with emphasis on how these impact HO-1 as a candidate therapeutic target in disease.
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5.
Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy.
Palka, J, Oscilowska, I, Szoka, L
Amino acids. 2021;(12):1917-1925
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Abstract
Recent studies on the regulatory role of amino acids in cell metabolism have focused on the functional significance of proline degradation. The process is catalysed by proline dehydrogenase/proline oxidase (PRODH/POX), a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate (P5C). During this process, electrons are transferred to electron transport chain producing ATP for survival or they directly reduce oxygen, producing reactive oxygen species (ROS) inducing apoptosis/autophagy. However, the mechanism for switching survival/apoptosis mode is unknown. Although PRODH/POX activity and energetic metabolism were suggested as an underlying mechanism for the survival/apoptosis switch, proline availability for this enzyme is also important. Proline availability is regulated by prolidase (proline supporting enzyme), collagen biosynthesis (proline utilizing process) and proline synthesis from glutamine, glutamate, α-ketoglutarate (α-KG) and ornithine. Proline availability is dependent on the rate of glycolysis, TCA and urea cycles, proline metabolism, collagen biosynthesis and its degradation. It is well established that proline synthesis enzymes, P5C synthetase and P5C reductase as well as collagen prolyl hydroxylases are up-regulated in most of cancer types and control rates of collagen biosynthesis. Up-regulation of collagen prolyl hydroxylase and its exhaustion of ascorbate and α-KG may compete with DNA and histone demethylases (that require the same cofactors) to influence metabolic epigenetics. This knowledge led us to hypothesize that up-regulation of prolidase and PRODH/POX with inhibition of collagen biosynthesis may represent potential pharmacotherapeutic approach to induce apoptosis or autophagic death in cancer cells. These aspects of proline metabolism are discussed in the review as an approach to understand complex regulatory mechanisms driving PRODH/POX-dependent apoptosis/survival.
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6.
Resveratrol as an Enhancer of Apoptosis in Cancer: A Mechanistic Review.
Ashrafizadeh, M, Taeb, S, Haghi-Aminjan, H, Afrashi, S, Moloudi, K, Musa, AE, Najafi, M, Farhood, B
Anti-cancer agents in medicinal chemistry. 2021;(17):2327-2336
Abstract
The resistance to therapy of cancer cells is a challenge for achieving an appropriate therapeutic outcome. Cancer (stem) cells possess several mechanisms for increasing their survival following exposure to toxic agents such as chemotherapy drugs, radiation, as well as immunotherapy. Evidences show that apoptosis plays a key role in the response of cancer (stem) cells and their multi-drug resistance. Modulation of both intrinsic and extrinsic pathways of apoptosis can increase the efficiency of tumor response and amplify the therapeutic effects of radiotherapy, chemotherapy, targeted therapy, and also immunotherapy. To date, several agents, as adjuvant, have been proposed to overcome the resistance of cancer cells to apoptosis. Natural products are interesting because of the low toxicity on normal tissues. Resveratrol is a natural herbal agent that has shown interesting anti-cancer properties. It has been shown to kill cancer cells selectively while protecting normal cells. Resveratrol can augment reduction/oxidation (redox) reactions, thus increases the production of ceramide and the expression of apoptosis receptors, such as Fas Ligand (FasL). Resveratrol also triggers some pathways which induce the mitochondrial pathway of apoptosis. On the other hand, resveratrol has an inhibitory effect on antiapoptotic mediators, such as Nuclear Factor κ B (NF-κB), Cyclooxygenase-2 (COX-2), Phosphatidylinositol 3- Kinase (PI3K), and mTOR. In this review, we explain the modulatory effects of resveratrol on apoptosis, which can augment the therapeutic efficiency of anti-cancer drugs or radiotherapy.
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Multiple interactions between melatonin and non-coding RNAs in cancer biology.
Maleki, M, Khelghati, N, Alemi, F, Younesi, S, Asemi, Z, Abolhasan, R, Bazdar, M, Samadi-Kafil, H, Yousefi, B
Chemical biology & drug design. 2021;(3):323-340
Abstract
The melatonin hormone secreted by the pineal gland is involved in physiological functions such as growth and maturation, circadian cycles, and biological activities including antioxidants, anti-tumor, and anti-ischemia. Melatonin not only interacts with proteins but also has functional effects on regulatory RNAs such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). In this study, we overview various physiological and pathological conditions affecting melatonin through lncRNA and miRNA. The information compiled herein will serve as a solid foundation to formulate ideas for future mechanistic studies on melatonin. It will also provide a chance to more clarify the emerging functions of the non-coding transcriptome.
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8.
Flavonoids as Anticancer Agents.
Kopustinskiene, DM, Jakstas, V, Savickas, A, Bernatoniene, J
Nutrients. 2020;(2)
Abstract
Flavonoids are polyphenolic compounds subdivided into 6 groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins found in a variety of plants. Fruits, vegetables, plant-derived beverages such as green tea, wine and cocoa-based products are the main dietary sources of flavonoids. Flavonoids have been shown to possess a wide variety of anticancer effects: they modulate reactive oxygen species (ROS)-scavenging enzyme activities, participate in arresting the cell cycle, induce apoptosis, autophagy, and suppress cancer cell proliferation and invasiveness. Flavonoids have dual action regarding ROS homeostasis-they act as antioxidants under normal conditions and are potent pro-oxidants in cancer cells triggering the apoptotic pathways and downregulating pro-inflammatory signaling pathways. This article reviews the biochemical properties and bioavailability of flavonoids, their anticancer activity and its mechanisms of action.
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A Compressive Review about Taxol®: History and Future Challenges.
Gallego-Jara, J, Lozano-Terol, G, Sola-Martínez, RA, Cánovas-Díaz, M, de Diego Puente, T
Molecules (Basel, Switzerland). 2020;(24)
Abstract
Taxol®, which is also known as paclitaxel, is a chemotherapeutic agent widely used to treat different cancers. Since the discovery of its antitumoral activity, Taxol® has been used to treat over one million patients, making it one of the most widely employed antitumoral drugs. Taxol® was the first microtubule targeting agent described in the literature, with its main mechanism of action consisting of the disruption of microtubule dynamics, thus inducing mitotic arrest and cell death. However, secondary mechanisms for achieving apoptosis have also been demonstrated. Despite its wide use, Taxol® has certain disadvantages. The main challenges facing Taxol® are the need to find an environmentally sustainable production method based on the use of microorganisms, increase its bioavailability without exerting adverse effects on the health of patients and minimize the resistance presented by a high percentage of cells treated with paclitaxel. This review details, in a succinct manner, the main aspects of this important drug, from its discovery to the present day. We highlight the main challenges that must be faced in the coming years, in order to increase the effectiveness of Taxol® as an anticancer agent.
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10.
Apoptosis in Autoimmunological Diseases, with Particular Consideration of Molecular Aspects of Psoriasis.
Krawczyk, A, Miśkiewicz, J, Strzelec, K, Wcisło-Dziadecka, D, Strzalka-Mrozik, B
Medical science monitor : international medical journal of experimental and clinical research. 2020;:e922035
Abstract
Apoptosis is a natural physiological process involving programmed cell death. Thanks to this process, it is possible to maintain the homeostasis of the body and the immune system. Dysfunctions of this mechanism lead to development of autoimmune diseases such as psoriasis; these diseases are chronic and treatment is extremely difficult. In psoriasis (a skin disease), apoptosis disorders are manifested by keratinocyte proliferation dysfunction. Autoimmune diseases coexisting with psoriasis include multiple sclerosis, autoimmune thyroid disease, and diabetes, but the common pathogenesis of these diseases is not fully understood. Given the heterogenous nature and chronic and recurrent course of psoriasis, the selection of an effective therapeutic strategy is still a problem. This literature review was focused on the process of apoptosis as a factor in the development of autoimmune diseases, with particular emphasis on psoriasis. The work also includes a review of therapeutic methods of psoriasis based on the latest literature.