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1.
Recent Research Progress in Taxol Biosynthetic Pathway and Acylation Reactions Mediated by Taxus Acyltransferases.
Wang, T, Li, L, Zhuang, W, Zhang, F, Shu, X, Wang, N, Wang, Z
Molecules (Basel, Switzerland). 2021;(10)
Abstract
Taxol is one of the most effective anticancer drugs in the world that is widely used in the treatments of breast, lung and ovarian cancer. The elucidation of the taxol biosynthetic pathway is the key to solve the problem of taxol supply. So far, the taxol biosynthetic pathway has been reported to require an estimated 20 steps of enzymatic reactions, and sixteen enzymes involved in the taxol pathway have been well characterized, including a novel taxane-10β-hydroxylase (T10βOH) and a newly putative β-phenylalanyl-CoA ligase (PCL). Moreover, the source and formation of the taxane core and the details of the downstream synthetic pathway have been basically depicted, while the modification of the core taxane skeleton has not been fully reported, mainly concerning the developments from diol intermediates to 2-debenzoyltaxane. The acylation reaction mediated by specialized Taxus BAHD family acyltransferases (ACTs) is recognized as one of the most important steps in the modification of core taxane skeleton that contribute to the increase of taxol yield. Recently, the influence of acylation on the functional and structural diversity of taxanes has also been continuously revealed. This review summarizes the latest research advances of the taxol biosynthetic pathway and systematically discusses the acylation reactions supported by Taxus ACTs. The underlying mechanism could improve the understanding of taxol biosynthesis, and provide a theoretical basis for the mass production of taxol.
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Transarterial chemoembolization plus sorafenib versus sorafenib for intermediate-advanced hepatocellular carcinoma: A meta-analysis comparing clinical outcomes.
Xie, Y, Tian, H, Xiang, B, Zhang, Y, Liu, J, Cai, Z, Xiang, H
Medicine. 2021;(33):e26958
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Abstract
BACKGROUND Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer and the second leading cause of cancer-related death worldwide, local and systemic therapies are beneficial for those who have more advanced disease or are not suitable for radical treatment. We aim to investigate the clinical outcomes of transarterial chemoembolization (TACE) plus sorafenib compared with sorafenib monotherapy for intermediate-advanced HCC. METHODS A systematic search according to preferred reporting items for systematic reviews and meta-analyses guidelines in the PubMed database was conducted from inception to December 31, 2020 for published studies comparing survival outcomes and tumor response between TACE + sorafenib and sorafenib alone for intermediate-advanced HCC. RESULTS Five eligible cohort studies and a randomized controlled trial with a total of 3015 patients were identified. We found that the TACE + sorafenib group had a significantly better overall survival (OS) (hazard ratio, 0.77; 95% confidence interval [CI] 0.66-0.88, P < .001) than those treated with sorafenib. Median OS ranged from 7.0 to 22.0 months with TACE + sorafenib and from 5.9 to 18.0 months with sorafenib. The combination of TACE + sorafenib had a significantly better time to progression (hazard ratio, 0.74; 95% CI 0.65-0.82, P < .001) than those treated with sorafenib. Median time to progression ranged from 2.5 to 5.3 months with TACE + sorafenib and from 2.1 to 2.8 months with sorafenib. The results showed the TACE + sorafenib group had a higher disease control rate (log odds ratio, 0.52; 95% CI 0.25-0.80, P = .0002), objective response rate (log odds ratio, 0.85; 95% CI 0.37-1.33, P = .0006) than sorafenib group. Hand-foot skin reaction, diarrhea, fatigue, vomiting, and alanine aminotransferase (ALT) elevation were common adverse events. The adverse events were similar between the 2 groups excluding elevated ALT. CONCLUSION Although the TACE + sorafenib group had a higher elevated ALT, the combination of TACE + sorafenib had an OS benefit compared with sorafenib in the treatment of intermediate-advanced HCC. Further research is necessary to affirm this finding and clarify whether certain subgroups benefit from different combinations between TACE and sorafenib.
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RPL41 sensitizes retinoblastoma cells to chemotherapeutic drugs via ATF4 degradation.
Geng, W, Ren, J, Shi, H, Qin, F, Xu, X, Xiao, S, Jiao, Y, Wang, A
Journal of cellular physiology. 2021;(3):2214-2225
Abstract
Retinoblastoma is the most common intraocular cancer with metastatic potential affecting infants and children. Although chemotherapy is available for retinoblastoma, side effects and drug resistance are frequent. Rpl41, encoding ribosomal protein L41 (RPL41), has been identified as a tumor suppressor gene, and its targeted degradation of activating transcription factor 4 (ATF4) produces an antitumor effect. The goal of the present study is to provide experimental evidence for the clinical application of a small peptide regimen in combination with chemotherapy for the treatment of retinoblastoma and to investigate the mechanism of their combined cytotoxicity. It was observed that treatment with the RPL41 peptide alone decreased the viability, migration, and invasion of retinoblastoma Y79 and Weri-Rb1 cells, in addition to promoting cell apoptosis and cell cycle arrest. Furthermore, RPL41 protein levels showed a significantly decreased trend in retinoblastoma specimens, whereas ATF4 protein levels tended to be increased. Mechanistically, ATF4 degradation as a result of RPL41 peptide treatment was observed in retinoblastoma Y79 and Weri-Rb1 cells. Most important, low-dose administration of the RPL41 peptide significantly enhanced the antitumor effect of carboplatin, and further analysis confirmed their synergistic effect as anti-retinoblastoma therapy, indicating that RPL41 sensitized Y79 and Weri-Rb1 retinoblastoma cells to carboplatin. Thus, our data provide a preclinical rationale for the exploration of the RPL41 peptide as a potential adjuvant to carboplatin treatment in retinoblastoma.
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Cytolethal distending toxin: from genotoxin to a potential biomarker and anti-tumor target.
Kailoo, S, Shreya, , Kumar, Y
World journal of microbiology & biotechnology. 2021;(9):150
Abstract
Cytolethal Distending Toxin (CDT) belongs to the AB toxin family and is produced by a plethora of Gram-negative bacteria. Eight human-affecting enteropathogens harbor CDT that causes irritable bowel syndrome (IBS), dysentery, chancroid, and periodontitis worldwide. They have a novel molecular mode of action as they interfere in the eukaryotic cell-cycle progression leading to G2/M arrest and apoptosis. CDT, the first bacterial genotoxin described, is encoded in a single operon possessing three proteins, CdtA, CdtB, and CdtC. CdtA and CdtC are needed for the binding of the CDT toxin complex to the cholesterol-rich lipid domains of the host cell while the CdtB is the active moiety. Sequence and 3D structural-based analysis of CdtB showed similarities with nucleases and phosphatases, it was hypothesized that CdtB exercises a biochemical function identical to both these enzymes. CDT is secreted through the outer membrane vesicles from the producing bacteria. It is internalized in the target cells via clathrin-dependent endocytosis and translocated to the host cell nucleus through the Golgi complex and ER. This study discusses the virulence role of CDT, causing pathogenicity by acting as a tri-perditious complex in the CDT-producing species with an emphasis on its potential role as a biomarker and an anti-tumor agent.
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Antiproliferative Effect of Colonic Fermented Phenolic Compounds from Jaboticaba (Myrciaria trunciflora) Fruit Peel in a 3D Cell Model of Colorectal Cancer.
Augusti, PR, Quatrin, A, Mello, R, Bochi, VC, Rodrigues, E, Prazeres, ID, Macedo, AC, Oliveira-Alves, SC, Emanuelli, T, Bronze, MR, et al
Molecules (Basel, Switzerland). 2021;(15)
Abstract
Jaboticaba is a Brazilian native berry described as a rich source of phenolic compounds (PC) with health promoting effects. PC from jaboticaba peel powder (JPP) have low intestinal bio-accessibility and are catabolized by gut microbiota. However, the biological implication of PC-derived metabolites produced during JPP digestion remains unclear. This study aimed to evaluate the antiproliferative effects of colonic fermented JPP (FJPP) in a 3D model of colorectal cancer (CRC) composed by HT29 spheroids. JPP samples fermented with human feces during 0, 2, 8, 24 or 48 h were incubated (10,000 µg mL-1) with spheroids, and cell viability was assessed after 72 h. Chemometric analyses (cluster and principal component analyses) were used to identify the main compounds responsible for the bioactive effect. The antiproliferative effect of FJPP in the CRC 3D model was increased between 8 h and 24 h of incubation, and this effect was associated with HHDP-digalloylglucose isomer and dihydroxyphenyl-γ-valerolactone. At 48 h of fermentation, the antiproliferative effect of FJPP was negligible, indicating that the presence of urolithins did not improve the bioactivity of JPP. These findings provide relevant knowledge on the role of colonic microbiota fermentation to generate active phenolic metabolites from JPP with positive impact on CRC.
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Combinations of Calcitriol with Anticancer Treatments for Breast Cancer: An Update.
Segovia-Mendoza, M, García-Quiroz, J, Díaz, L, García-Becerra, R
International journal of molecular sciences. 2021;(23)
Abstract
Preclinical, clinical, and epidemiological studies indicate that vitamin D3 (VD) deficiency is a risk factor for the development of breast cancer. Underlying mechanisms include the ability of calcitriol to induce cell differentiation, inhibit oncogenes expression, and modify different signaling pathways involved in the control of cell proliferation. In addition, calcitriol combined with different kinds of antineoplastic drugs has been demonstrated to enhance their beneficial effects in an additive or synergistic fashion. However, a recognized adjuvant regimen based on calcitriol for treating patients with breast cancer has not yet been fully established. Accordingly, in the present work, we review and discuss the preclinical and clinical studies about the combination of calcitriol with different oncological drugs, aiming to emphasize its main therapeutic benefits and opportunities for the treatment of this pathology.
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Cisplatin-induced nephrotoxicity in children: what is the best protective strategy?
Ruggiero, A, Ariano, A, Triarico, S, Capozza, MA, Romano, A, Maurizi, P, Mastrangelo, S, Attinà, G
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2021;(1):180-186
Abstract
INTRODUCTION Platinum compounds, which are considerably effective for the treatment of childhood malignancies, have significantly contributed to the increase in long-term survival of children with cancer. Unfortunately, children receiving cisplatin-based chemotherapy have been known to be at risk for severe disabling adverse effects, such as nephrotoxicity. METHODS A literature research of the MEDLINE PubMed database was conducted to identify articles published between 1980 and 2019 reviewing "Cisplatin AND mannitol." RESULTS The primary pharmacodynamics and clinical characteristics of cisplatin were described, focusing on its renal toxic effects and potential preventive strategies, in order to improve clinical outcomes among children with cancer aged 1 to 14 years. Currently, selecting either hydration alone or hydration plus mannitol for preventing nephrotoxicity has been controversial considering the lack of guidelines to provide treatment recommendations both among adults and children. CONCLUSIONS Appropriate knowledge regarding the pharmacokinetics and toxicological profile of cisplatin may help physicians prevent renal toxicity. Unfortunately, published data regarding the nephroprotective utility of adding mannitol appear to be inconclusive. As such, appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. Considering the increasing number of children safely cured of their tumours, it is imperative that those treated with cisplatin receive the most appropriate nephroprotective strategy for reducing the negative impact of platinum compounds on quality of life.
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The interaction between lipocalin 2 and dipyridine ketone hydrazone dithiocarbamte may influence respective function in proliferation and metastasis-related gene expressions in HepG2 cell.
Li, C, Li, Y, Lou, L, Han, X, Wang, H, Huang, T, Li, C
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2021;(1):123-133
Abstract
LCN2 (Lipocalins) was first identified as iron transporter through associating with its siderophores and also involved in many cancer metastases, but its function is still paradoxical. We questioned that whether LCN2 might also associate exogenous iron chelator as does in inherent way and the association may influence their respective function. To address this issue, we investigated the effect of LCN2 on action of DpdtC (2,2'-dipyridine ketone hydrazone dithiocarbamte), an iron chelator in proliferation and metastasis-related gene expression. The results showed that exogenous LCN2 and DpdtC could inhibit growth of HepG2 cells, while the combination treatment enhanced their inhibitory effect both in proliferation and colony formation. This encouraged us to investigate the effect of the interaction on metastasis-related gene expression. The results revealed that both LCN2 and DpdtC impaired the wound healing of HepG2, but the inhibitory effect of DpdtC was significantly enhanced upon association with LCN2. Undergoing epithelium-mesenchymal transition (EMT) is a crucial step for cancer metastasis, LCN2 and DpdtC had opposite effects on EMT markers, the binding of DpdtC to LCN2 significantly weakened the regulation of it (or its iron chelate) on EMT markers. To insight into the interaction between LCN2 and DpdtC-iron, fluorescence titration and molecular docking were performed to obtain the association constant (~ 104 M-1) and thermodynamic parameters (ΔG = - 26.10 kJ/mol). Importantly this study provided evidence that siderophores-loading state of LCN2 may influence its function, which be helpful for understanding the contradictory role of LCN2 in the metastasis of cancer.
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The Efficacy and Safety of Anlotinib in Neoadjuvant Treatment of Locally Advanced Thyroid Cancer: A Single-Arm Phase II Clinical Trial.
Huang, NS, Wei, WJ, Xiang, J, Chen, JY, Guan, Q, Lu, ZW, Ma, B, Sun, GH, Wang, YL, Ji, QH, et al
Thyroid : official journal of the American Thyroid Association. 2021;(12):1808-1813
Abstract
Background: Surgery is the primary treatment for locally advanced thyroid cancer. For some cases, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. Anlotinib is a multitarget tyrosine kinase inhibitor, which demonstrated antitumor activity in radioiodine-refractory differentiated thyroid cancer and medullary thyroid cancer. We aimed to evaluate the efficacy and safety of anlotinib in locally advanced thyroid cancer in the neoadjuvant setting. Methods: This single-arm phase II study investigated the efficacy and safety of anlotinib (12 mg orally daily, 2 weeks on/1 week off) for 2-6 cycles in patients with locally advanced thyroid cancer in the neoadjuvant setting. The key eligibility criteria included age 14-80 years old; locally advanced thyroid cancer that would benefit from surgery, and at least one measurable lesion. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were enrolled and received an average of 3.5 cycles of anlotinib treatment. The ORR of anlotinib was 76.9% (95% confidence interval: 46.2-95.0%). The R0/R1 resection rate in the intent-to-treat population was 61.5% and in the per-protocol population was 72.7%. The median time to response was 61.5 days, and the disease control rate at 18 weeks was 92.3%. No patients had blood transfusion or tracheotomy. Most adverse events (AEs) were grade 1 or 2 and tended to discontinue when neoadjuvant treatment ceased. Common AEs of all grades were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), thyrotropin increase (53.8%), cholesterol elevation (53.8%), and hand-foot syndrome (38.5%). Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment and the majority of patients achieved R0/R1 resection. AEs were consistent with the known anlotinib AE profile. These results suggest that anlotinib neoadjuvant treatment represents a new option for locally advanced thyroid cancer. Clinical Trial Registration Number: NCT04309136.
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Multikinase inhibitors in thyroid cancer: timing of targeted therapy.
Gild, ML, Tsang, VHM, Clifton-Bligh, RJ, Robinson, BG
Nature reviews. Endocrinology. 2021;(4):225-234
Abstract
In the 9 years since the publication of our 2011 review of targeted treatment of thyroid cancer with multikinase inhibitors, much has changed in the landscape of this heterogeneous disease. New multikinase and selective inhibitor treatments for medullary thyroid cancer, radioiodine-refractory thyroid cancer and anaplastic thyroid cancer have completed trials and improved progression-free survival. Many physicians are concerned by dose-limiting adverse effects of these drugs and are wary to begin treatment in patients who are systemically well but have marked disease burden, which makes the timing of treatment initiation challenging. Published mechanistic data on tyrosine kinase inhibitors (TKIs) have helped guide our understanding of how to dose effectively with these drugs. A major goal in TKI therapy is to optimize inhibition of oncogenic kinase drivers while maintaining patient quality of life. Real-world data have now been published on how TKIs have fared outside the clinical trial environment. In this Review, we provide a summary of published data on the efficacy of TKIs in clinical practice, to provide clinicians with a more realistic view of how their patients will manage and respond to TKI therapy. Furthermore, we review the data on mechanisms of inhibition, outcomes and adverse effects of TKIs and provide an update on targeted treatment of thyroid cancer, focusing on optimizing the timing of treatment initiation.