Role In Anticancer Therapy Research Articles

Abstract 2534: Targeting defective necroptosis in colorectal cancer to overcome therapeutic resistance

Abstract Colorectal cancer (CRC) is a leading cause of cancer related deaths in the United States. CRC patients are often treated with the chemotherapeutic drug 5-fluorouracil (5-FU), but resistance often occurs. It is well-established that 5-FU induces apoptosis in cancer cells, but apoptosis inhibition does not block the anticancer effect of 5-FU, suggesting a role of non-apoptotic cell death. Necroptosis is a regulated form of necrosis controlled by Receptor-Interacting Protein kinase 1 (RIP1), RIP3, and Mixed Lineage Kinase domain-Like (MLKL), and its role in anticancer therapy remains unclear. TCGA RNAseq data show that RIP3 is significantly downregulated in primary CRC tumors, which is correlated with worse outcomes. RIP3 downregulation also occurs in established CRC cell lines and is associated with decreased 5-FU sensitivity. Therefore, we hypothesize that necroptosis may play a critical role in anticancer therapy and that restoring defective necroptosis may enhance therapeutic sensitivity. Our studies show that RIP3-expressing (RIP3+) CRC cells undergo both apoptosis and necroptosis in response to 5-FU. As expected, knock-out of RIP3 in RIP3+ CRC cells resulted in decreased 5-FU sensitivity, as well as abrogated necroptosis induction. Additionally, stable restoration of RIP3 in RIP3-silenced (RIP3-) CRC cells appeared to enhance 5-FU response, under conditions where apoptosis was inhibited. Furthermore, we explored alternative ways to induce necroptosis in RIP3-silenced cells. Together, our results suggest that necroptosis plays an important role in 5-FU-induced cell death in CRC. These results provide novel insights into the role of necroptosis in anticancer therapy in CRC, which could be used for development of improved therapies and personalized medicine based on RIP3 status. Citation Format: Kaylee Ermine, Dongshi Chen, Xinyan Lu, Jian Yu, Lin Zhang. Targeting defective necroptosis in colorectal cancer to overcome therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2534.

Abstract 6773: Spatial dynamics of cytotoxic T lymphocyte exhaustion in reactive and tumoral tissue

Abstract Background The study of cytotoxic T-lymphocytes (Tcy) has shown increased attention from the scientific community in the last years because of their predictive role in anti-cancer therapy with specific interest in immune check point blocking therapy. However, most of these studies have used bulk or dissociation-based single-cell technologies to draw their biological insights. Lately, new spatial -omics technologies are increasing our knowledge on this population by adding the spatial location of these cells in-situ in the native structure of the tissue. In this study, we have compared the activation of Tcy in reactive and cancerous conditions at single cell level and in the micro-anatomical context of the tissue. Experimental procedures One tissue micro array slide containing: reactive tonsil, inflammatory liver disease, breast cancer, glioblastoma and melanoma was stained using the COMET™ instrument (Lunaphore Technologies SA) for a multiplex panel of 20 markers. The derived multiplexed images were analyzed using the DISSCOVERY software platform developed by the MILAN Unit at KU Leuven (Belgium). 12/20 markers were specifically aimed at identifying the main cell populations in the tissue (CD11b, CD163, CD20, CD3, CD31, CD4, CD56, CD68, CD8, CK, FOXP3, S100) while the remaining 8 markers were aimed at adding functional information on immune cell types of interest (CD69, HLA-DR, Ki67, LAG3, OX40, PD-1, PD-L1, TIM3). Results The general activation levels of the Tcy in the reactive conditions were higher than in the three cancer subtypes. When looking at Tcy activation as a function of the distance from the vascular structures (identified via CD31+ endothelial cells), we observed an orderly distribution of activated Tcy around CD31+ endothelial cells with a gradient of increasing exhaustion levels with increasing distance from the vessel in the reactive conditions. In the cancer samples, on the contrary, a patchy disorderly organized pattern of exhausted and activated Tcy was observed around the vessels. Conclusion The spatial location of inflammatory cells plays a critical role to understand their functional behavior and thanks to technological progress it is now possible to start doing this at scale. The study of the dynamics of exhaustion of Tcy in the tissue will help clarify the interplay between cancer cells and immune environment. These results will be crucial to better select patients who may benefit the most of immune check point blockade. Citation Format: Maxim De Schepper, Asier Antoranz, Nikolina Dubroja, Giuseppe Floris, Frederik De Smet, Francesca Bosisio. Spatial dynamics of cytotoxic T lymphocyte exhaustion in reactive and tumoral tissue. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6773.

Lenvatinib Induces Immunogenic Cell Death and Triggers Toll-Like Receptor-3/4 Ligands in Hepatocellular Carcinoma.

Immunogenic cell death (ICD) is a cell death modality that plays a vital role in anticancer therapy. In this study, we investigated whether lenvatinib induces ICD in hepatocellular carcinoma and how it affects cancer cell behavior. Hepatoma cells were treated with 0.5 μM lenvatinib for two weeks, and damage-associated molecular patterns were assessed using the expression of calreticulin, high mobility group box 1, and ATP secretion. Transcriptome sequencing was performed to investigate the effects of lenvatinib on hepatocellular carcinoma. Additionally, CU CPT 4A and TAK-242 were used to inhibit TLR3 and TLR4 expressions, respectively. Flow cytometry was used to assess PD-L1 expression. Kaplan-Meier and Cox regression models were applied for prognosis assessment. After treatment with lenvatinib, there was a significant increase in ICD-associated damage-associated molecular patterns, such as calreticulin on the cell membrane, extracellular ATP, and high mobility group box 1, in hepatoma cells. Following treatment with lenvatinib, there was a significant increase in the downstream immunogenic cell death receptors, including TLR3 and TLR4. Furthermore, lenvatinib increased the expression of PD-L1, which was later inhibited by TLR4. Interestingly, inhibiting TLR3 in MHCC-97H and Huh7 cells strengthened their proliferative capacity. Moreover, TLR3 inhibition was identified as an independent risk factor for overall survival and recurrence-free survival in patients with hepatocellular carcinoma. Our study revealed that lenvatinib induced ICD in hepatocellular carcinoma and upregulated PD-L1 expression through TLR4 while promoting cell apoptosis through TLR3. Antibodies against PD-1/PD-L1 can enhance the efficacy of lenvatinib in the management of hepatocellular carcinoma.

Phthalimides Represent a Promising Scaffold for Multi‐Targeted Anticancer Agents

AbstractFrom the last two decades, phthalimide analogues received prime interest from scientists due to its potent inhibitory action on different cancer‐causing receptors. A variety of anticancer drugs are coming into the market but challenges of drug resistance, toxicities, and failure in therapy still remain. Cancer is a group of complex disorders it involves multiple receptors. So there is a need of targeting multiple receptors to get desired potent anticancer drugs with minimum harmful effects. Phthalimide scaffolds fit into these criteria as it is extensively reported for the inhibition of different cancer receptors such as VEGFR, HDAC, EGFR, TNF‐α, etc. The multi‐targeted mechanism of phthalimide derivatives plays a major role in anticancer therapy. Due to this advantage, there is the hope of developing some novel effective multi‐targeted anticancer agents. Consider structural features and pharmacological advancement of phthalimide analogues may fulfill the current need of cancer patients. In this review, we covered history, chemistry, SAR, anticancer mechanisms, and the current status of phthalimide derivatives reported till 2022. The article specifically focused on different cancer‐causing receptors inhibited by phthalimide derivatives and their mechanism of action in brief. Finally, we provided the future scope and role of phthalimide derivatives in multi‐targeted anticancer drug discovery.

Phytochemical Analysis and Anticancer Properties of Drimia maritima Bulb Extracts on Colorectal Cancer Cells.

Cancer is a worldwide health problem and is the second leading cause of death after heart disease. Due to the high cost and severe side effects associated with chemotherapy treatments, natural products with anticancer therapeutic potential may play a promising role in anticancer therapy. The purpose of this study was to investigate the cytotoxic and apoptotic characteristics of the aqueous Drimia maritima bulb extract on Caco-2 and COLO-205 colorectal cancer cells. In order to reach such a purpose, the chemical composition was examined using the GC-MS method, and the selective antiproliferative effect was determined in colon cancer cell lines in normal gingival fibroblasts. The intracellular ROS, mitochondrial membrane potential, and gene expression changes in selected genes (CASP8, TNF-α, and IL-6 genes) were assessed to determine the molecular mechanism of the antitumor effect of the extract. GC-MS results revealed the presence of fifty-seven compounds, and Proscillaridin A was the predominant secondary metabolite in the extract. The IC50 of D. maritima bulb extract on Caco-2, COLO-205, and the normal human gingival fibroblasts were obtained at 0.9 µg/mL, 2.3 µg/mL, and 13.1 µg/mL, respectively. The apoptotic effect assay indicated that the bulb extract induced apoptosis in both colon cancer cell lines. D. maritima bulb extract was only able to induce statistically significant ROS levels in COLO-205 cells in a dose-dependent manner. The mitochondrial membrane potential (MMP) revealed a significant decrease in the MMP of Caco-2 and COLO-205 to various concentrations of the bulb extract. At the molecular level, RT-qPCR was used to assess gene expression of CASP8, TNF-α, and IL-6 genes in Caco-2 and COLO-205 cancer cells. The results showed that the expression of pro-inflammatory genes TNF-α and IL-6 were upregulated. The apoptotic initiator gene CASP8 was also upregulated in the Caco-2 cell line and did not reach significance in COLO-205 cells. These results lead to the conclusion that D. maritima extract induced cell death in both cell lines and may have the potential to be used in CRC therapy in the future.

Role of vinca alkaloids and their derivatives in cancer therapy

Vinca alkaloids and its derivatives like Vincristine, Vinblastine etc. isolated from Catharanthus roseus plants are widely used in the treatment of various types of cancers. Mode of action of Vinca alkaloids (vinblastine, vincristine, vinorelbine) is microtubule-stabilizing agents (MTAs) i.e., arrest the cell cycle via disrupting microtubule dynamics. Vincristine major side effect is neurotoxicity. Hoverer, Vincristine induce neuropathy in mice or rat, used as animal model to study effect of drugs or plants by various authors also reported in review literature. Vinca alkaloids and its derivatives were widely used drugs in combination regimens with cyclophosphamide, doxorubicin, procarbazine, Methotrexate and dacarbazine etc. in various types of cancer. In this review, we also discussed major structure modifications position of chemically synthesized vincristine and vinblastine derivatives required for potential anticancer activities. Anticancer mechanism and some major patents on vinca alkaloids derivatives also reported in this review article. The study of Vinca alkaloids and its derivatives a class of an antimitotic compounds, found essential role in anticancer therapies.

Abstract A015: Targeting necroptosis and RIP3 in colorectal cancer to overcome chemotherapeutic resistance

Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. When metastatic, chemotherapeutic drug 5-fluorouracil (5-FU) is typically used for treatment, but resistance often occurs. Many studies have shown that 5-FU induces apoptosis in cancer cells, but when apoptosis is inhibited, cell death can still occur, suggesting that other forms of cell death are occurring. Necroptosis, or regulated necrosis, is an alternative form of cell death, controlled by RIP1, RIP3, and MLKL, and its role in anticancer therapy remains unclear. TCGA RNAseq data show that RIP3 is significantly downregulated in primary CRC tumors, with RIP3 downregulation correlating with worse clinical outcomes. Analysis of numerous established CRC cell lines revealed that RIP3 expression was downregulated in ~50% of the cell lines, with low RIP3 expression being associated with decreased 5-FU sensitivity. These data led us to hypothesize that RIP3 expression and necroptosis may play a critical role in response to anticancer therapies, such as 5-FU, and that restoring defective necroptosis may enhance therapeutic sensitivity. Our preliminary studies have shown that RIP3-expressing (RIP3+) CRC cell lines are able to undergo both apoptosis and necroptosis in response to 5-FU, which could explain the enhanced sensitivity. As expected, knock-out of RIP3 in RIP3+ cells resulted in decreased 5-FU sensitivity, as well as abrogated necroptosis induction. Additionally, transient restoration of RIP3 in RIP3-silenced (RIP3-) CRC cells appeared to enhance 5-FU sensitivity, and so, we generated a stable RIP3-expressing cell line through retroviral infection. Although the stable RIP3-expressing cell line did not appear to be more sensitive to 5-FU alone, it did show enhanced sensitivity under conditions where apoptosis is inhibited. Together, our results suggest that RIP3 plays an important role in 5-FU-induced cell death in CRC, and that restoring RIP3 when the apoptosis pathway is implicated could provide a way to enhance 5-FU sensitivity and overcome resistance. The results from this project provide novel insight into the role of RIP3 in mediating response to anticancer therapy in CRC, which could be used for development of improved therapies and personalized medicine based on RIP3 status in the clinic. Citation Format: Kaylee A. Ermine, Dongshi Chen, Peng Wang, Jian Yu, Lin Zhang. Targeting necroptosis and RIP3 in colorectal cancer to overcome chemotherapeutic resistance [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A015.

Role of non-coding RNA in immune microenvironment and anticancer therapy of gastric cancer.

Gastric cancer remains one of the cancers with the highest mortality in the world; therefore, it is very important to investigate its pathogenesis to improve the prognosis of gastric cancer patients. Recently, noncoding RNAs have become a research hotspot in the field of oncology. These RNA molecules play complex roles in the regulation of tumor cells, immune cells, and the tumor microenvironment. Therefore, studying their ability to regulate the gastric cancer immune microenvironment will provide us with a better perspective to understand their potential role in anticancer therapy. In this review, we discuss the regulatory effects of several common noncoding RNAs on the immune microenvironment of gastric cancer and their prospects in anticancer therapy to provide some novel insight into the identification of valuable diagnostic markers and improving the prognosis of gastric cancer patients.

Abstract 624: Classifying cGAS-STING activity links chromosomal instability with immunotherapy response in metastatic bladder cancer

Abstract The cGAS-STING pathway serves a critical role in anti-cancer therapy. Particularly, response to immunotherapy is likely driven by both active cGAS-STING signaling that attracts immune cells, and by the presence of cancer neoantigens that presents as targets for cytotoxic T-cells. Chromosomal instability (CIN) is a hallmark of cancer, but also leads to an accumulation of cytosolic DNA that in turn results in increased cGAS-STING signaling. To avoid triggering the cGAS-STING pathway, it is commonly disrupted by the cancer cells, either through mutations in the pathway or through transcriptional silencing. Given its effect on the immune system, determining the cGAS-STING activation status prior to treatment initiation is likely of clinical relevance, but to date no robust method has been developed. Here, we used combined expression data from 2307 tumors from five cancer types from The Cancer Genome Atlas (TCGA) to define a novel cGAS-STING activity score based on eight genes with a known role in the pathway. Using unsupervised clustering, four distinct categories of cGAS-STING activation were identified. In multivariate models, the cGAS-STING active tumors show improved prognosis. Importantly, in an independent bladder cancer immunotherapy treated cohort, patients without cGAS-STING activation showed very limited response to treatment, while patients with strong cGAS-STING activation showed improved response and improved prognosis, particularly among patients with high CIN and high numbers of neoantigens. In a multivariate model, a significant interaction was observed between CIN, neoantigens, and cGAS-STING activation. Together, this supports a role of cGAS-STING activity as a predictive biomarker in combination with measures of CIN and neoantigens for the application of immunotherapy. Citation Format: Mateo Sokac. Classifying cGAS-STING activity links chromosomal instability with immunotherapy response in metastatic bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 624.

Curcumin and its Anti-Cancer Properties: Kitchen to the Laboratory

Curcumin is a naturally derived hydrophobic polyphenolic compound extracted from the rhizome (turmeric) of the herb Curcumalonga. It has been used as a common Indian spice in the form of turmeric since time immemorial. Curcumin is an active ingredient ofturmeric and has been found to have many health benefits.Our main aim is to highlight curcumin's biological activity and anti-cancer properties.Curcumin is a bright yellow-colored substance; curcumin plays a vital role in anti-cancer therapy by suppressing cell proliferationand metastasis. Curcumin has regulatory effects on secondary signaling molecules and the further downstream process leading toregulation of transcription factors like nuclear factor-kappa light chain enhancer of activated B cell or NF-kB. Cancer cells have enhancedtelomerase activity; therefore, their DNA never shortens due to the loss of telomeres. Curcumin initiates p53 protein-dependent andprotein-independent G2/M phase cell cycle arrest. Curcumin has plenty of targets like growth factor receptors (Epidermal GrowthFactor Receptor or EGFR), enzymes, and cytokines. Curcumin has poor bioavailability due to its low solubility in water (0.0004mg/mL atnormal pH 7) and hence produces poor effects when administered orally. Curcumin also produces toxicity in patients when consumedin high concentrations.The 21st century is the age of technology. We see that nanotechnology has enabled us to design curcumin-encapsulated, which reducesits bulk size and brings it within 100 nm. Particles like liposomes (phospholipid vesicles), polymer micelles, SLNs, and microspheresare some drug target delivery systems that can solve problems of transporting curcumin. Nanocurcumins can also be extracted frompure curcumin without any carriers. It is under clinical trial where curcumin has been used as an adjuvant with other chemical agentsto control the spread of cancer.

From tryptophan to novel mitochondria-disruptive agent, synthesis and biological evaluation of 1,2,3,6-tetrasubstituted carbazoles

Mitochondrial targeting plays an important role in anticancer therapy. The Mn(III)-promoted cyclization of 5-(1H-indol-3-yl)-3-oxopentanoic acid allow to obtain novel substituted carbazole derivatives that can act as mitochondria-disruptive agents. The starting materials used for the synthesis of these new aminocarbazoles are oxopentanoate derivatives of tryptophan. The scope and limitation of this method of synthesis are determined by a series of experiments. The prepared carbazole derivatives are screened for their in vitro anticancer activity against a broad panel of human cancer cells and normal cell lines. Among the tested compounds, the most active ones are examined further against human colon cancer cells (HCT-116) and human bone osteosarcoma (U-2 OS), in complex in vitro cellular assays, including studies on cell cycle distribution, intracellular compartmentalization, antimigratory properties, mitochondrial generation of reactive oxygen species, DNA damage, and type of cellular death. The results reveal that the synthesized compounds display potent oxidative activity inducing massive accumulation of DNA double-strand breaks, which lead to a parallel change in the assembly of mitochondria causing their dysfunction. These findings provide new leads for the treatment of colon cancer and osteosarcoma.

CAR-macrophage: An extensive immune enhancer to fight cancer.

CAR-macrophage: An extensive immune enhancer to fight cancer.

Molecular Analysis of Prognosis and Immune Pathways of Pancreatic Cancer Based on TNF Family Members.

Background Tumor necrosis factor (TNF) family members play a vital role in anticancer therapy. This study aimed to screen the critical markers for the prognostic analysis of pancreatic adenocarcinoma (PAAD) by analyzing the clustering patterns of TNF family members in PAAD. Methods In this study, the NMF clustering method was adopted to cluster samples from The Cancer Genome Atlas (TCGA) to acquire the clustering pattern of the TNF family in PAAD. Differential gene analysis was performed according to TNF family gene clusters. The support vector machine (SVM) method was conducted for further gene screening, and the risk score model of the screened genes was constructed by Lasso. The single sample gene set enrichment analysis (ssGSEA) method was adopted for immunoenrichment analysis and tumor immune cycle analysis. Genes associated with risk scores were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results We clustered PAAD into two groups based on TNF family genes. Nineteen TNF family genes were significantly associated with the clinical characteristics of PAAD patients. The risk score formula was composed of RHOD, UBE2C, KLHDC7b, MSLN, ADAM8, NME3, GNG2, and MCOLN3. GSE57495 and GSE62452 datasets verified that patients in the high-risk group had a worse prognosis than those in the low-risk group. The risk score-related genes analyzed by GO and KEGG were mainly involved in the modulation of chemical synaptic transmission and synaptic vesicle cycle pathway. There were significant differences in the expression of 15 immune cells between the high-risk group and the low-risk group. The risk score was positively correlated with HCK, interferon, MHC-I, and STAT1. The expression of genes relevant to chemokine, immunostimulator, MHC, and receptor was strongly associated with the risk score. Conclusion The risk score model based on the TNF family can predict the prognosis and immune status of PAAD patients. Further research is needed to verify the clinical prognostic value of risk scores.

Chalcone Derivatives: Role in Anticancer Therapy.

Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.

Relation between Gut Microbiota and Cancer

Human has about 100 trillion symbiotic microbes in the gut with 300-1000 different species. Gut microbiota is associated with host metabolism, obesity, diabetes, hepatic disorder, and cancer. Nowadays, studies are focusing on the role of gut microbiota in cancer. Evidence shows that Fusobacterium is associated with colorectal cancer when its genome was confirmed by 16SRNA analysis and PCR technique in cancerous cell. The complete mechanism of gut microbe involvement in cancer is still unknown. There may be some association of toxic metabolites of gut microbes, dietary substances, and the immune response. This review will help to attain the brief knowledge about the research till now in the regard of gut microbiota with cancer. The study will also reveal the research of using gut microbes for anticancer therapy. It is examined that Lactobacillus rhamnosus in the form of probiotics has a significant role in anticancer therapy. The anticancerous therapeutic and immunogenic role of gut microbiota must be further studied.

Induction of Caspase-Mediated Apoptosis in HepG2 Liver Carcinoma Cells Using Mutagen-Antioxidant Conjugated Self-Assembled Novel Carbazole Nanoparticles and In Silico Modeling Studies.

In this study, novel self-assembled carbazole-thiooctanoic acid nanoparticles (CTNs) were synthesized from amino carbazole (a mutagen) and thiooctanoic acid (an antioxidant). The nanoparticles were characterized using hyperspectral techniques. Then, the antiproliferative potential of CTNs was determined in HepG2 liver carcinoma cells. This study employed a solvent–antisolvent interaction method to synthesize a spherical CTN of size less than 50 nm. Moreover, CT was subsequently capped to gold nanoparticles (AuNPs) in the additional comparative studies. The CT derivative was synthesized from carbazole and lipoic acid by the amide bond formation reaction using a coupling agent. Furthermore, it was characterized using infrared (IR), 1H nuclear magnetic resonance, dynamic light scattering (DLS), and transmission electron microscopy techniques. The CT-capped gold nanoparticles (CTAuNPs) were prepared from CT, chloroauric acid, and NaBH4. The CTAuNPs were characterized using ultraviolet–visible, high-resolution TEM, DLS, and Fourier transform IR techniques. The cytotoxicity and apoptosis-inducing ability of both nanoparticles were determined in HepG2 cells. The results demonstrate that CTNs exhibit antiproliferative activity in the cancerous HepG2 cells. Moreover, molecular docking and molecular dynamics studies were conducted to explore the therapeutic potential of CT against human EGFR suppressor protein to gain more insights into the binding mode of the CT, which may show a significant role in anticancer therapy.

Alterations of DNA damage repair in cancer: from mechanisms to applications.

DNA damage repair (DDR) pathways are essential to ensure the accurate transmission of genetic material. However, different endogenous and exogenous factors challenge genomic integrity. Mechanisms involved in the alterations of DDR pathways mainly include genetic inactivation and epigenetic mechanisms. The development and progression of carcinomas are closely associated with DDR pathway aberrations, including the epigenetic silencing of gene O6-alkylguanine-DNA methyltransferase (MGMT); deficiencies of mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS protein homologue (MSH)-2 (MSH2), MSH6, and PMS1 homolog 2; the mismatch repair system component (PMS2); and mutations of homologous recombination repair (HRR) genes, such as the breast cancer susceptibility gene 1/2 (BRCA1/2). Understanding the underlying mechanisms and the correlations between alterations to DDR pathways and cancer could improve the efficacy of antitumor therapies. Emerging evidence suggests that survival is higher in patients with DDR-deficient tumors than in those with DDR-proficient tumors. Thus, DDR alterations play a predictive and prognostic role in anticancer therapies. Theoretical studies on the co-administration of DDR inhibitors and other anticancer therapies, including chemotherapy, radiotherapy, immunotherapy, endocrine therapy, and epigenetic drugs, hold promise for cancer treatments. In this review, we focus on the basic mechanisms, characteristics, current applications, and combination strategies of DDR pathways in the anticancer field.

Protein Kinase Structure, Function, and its Binding Sites for Understanding the Role in Anticancer Therapy

Background: Protein kinases are involved in regulating different aspects of metabolism including cell growth, differentiation and regulation of cell cycle. Deregulated protein kinases are thought to affect various forms of tumor growth. The advent of protein kinase inhibitors has caused a great shift in the way we treat cancer. Purpose: There were several inhibitors of protein kinases that had been approved by the FDA in the last few decades. Therefore the need of the hour is to know the structure of the protein kinase to design the effective therapy for cancer treatment. Interaction of the drug with the protein is successful if the drug binds to the cavity of the receptor or protein and brings conformational changes, therefore the binding site in the protein should be well understood. Conclusion: Thus in this mini review we have systematically discussed the structure of protein kinase and their binding sites so the future designing of the potential molecules should have better efficacy.

Prognostic Importance Of The Use Of Glucocorticoids And Antibiotics During The Neoadjuvant Radiotherapy Treatment In Locally Advanced Rectal Cancer: An Observational Study

There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Current studies have reported that the use of glucocorticoids and antibiotics therapy is associated with a reduced response to immune checkpoint inhibitors (ICIs) in routine practice. The purpose of this study was to evaluate whether there is an association between antibiotics and glucocorticoids administered during neoadjuvant radiotherapy (NRT) and prognosis in patients with local advanced rectal cancer (LARC) in routine clinical practice. We reviewed patients with pathologically confirmed LARC undergoing NRT followed by surgery in our department between January 2012 and April 2017. Collect patients' medication for glucocorticoids and antibiotics from the beginning of treatment and before surgery by consulting the electronic medical advice system. The patients were divided into four groups according to the time of the first glucocorticoids medication: no medication (noGC), before the start of NRT (bNRT), the first half of total NRT treatment time (fNRT), and the second half of total NRT treatment time until the operation (sNRT). We investigated whether glucocorticoids and antibiotics therapy administered during 30 days before NRT therapy until surgery was associated with overall survival (OS) and disease-free survival (DFS). Among 793 LARC patients (504 men and 289 women; median [range] age, 56 [49-63] years) with glucocorticoids therapy (n = 344, 43.3%) and antibiotics therapy (n = 320, 40.3%). Multivariate cox proportional hazards model analysis demonstrated that glucocorticoid therapy was associated with worse OS (hazard ratio [HR], 1.652; 95%CI, 1.115-2.447) and DFS (HR, 1.490; 95%CI, 1.028-2.160), but there were no significant differences in OS and DFS among patients with antibiotics therapy or not. Furthermore, there were significant differences in OS (HR, 2.071; 95%CI, 1.303-3.290, p = 0.002) among patients with glucocorticoid therapy in fNRT vs. noGC, but not in bNRT or fNRqazwT vs. noGC. fNRT vs. noGC. The dose of glucocorticoids was significantly associated with the DFS (HR, 1.935; 95%CI, 1.188-3.151, p = 0.008) in ≥35mg vs. noGC, but not in <35mg vs. noGC. Multivariate analyses confirmed that glucocorticoid therapy in fNRT was associated with worse OS (HR, 1.790; 95%CI, 1.186-2,701, p = 0.006) and high dose (≥35mg) were also associated with worse DFS (HR, 1.736; 95%CI, 1.105-2.728, p = 0.017) as potential independent prognostic factors. This study suggests that glucocorticoid therapy but not antibiotics therapy is associated with a worse OS and DFS in LARC patients in routine clinical practice. Glucocorticoid therapy in fNRT and high dose (≥35mg) are independent risk factors for OS and DFS, respectively. Mechanistic studies are urgently required to investigate glucocorticoids-mediated alterations of the immune response as a determinant of poorer outcome following NRT treatment.

Mechanism of mitotic catastrophe and its role in anticancer therapy

The definition of mitotic catastrophe has been the subject of scientific discussion for over a decade. Initially, it was thought that mitotic catastrophe is one of the types of cell death occurring during aberrant mitosis. A number of studies carried out in recent years allowed for a better understanding of the function of this process. According to the definition proposed by the Nomenclature Committee on Cell Death in 2018, mitotic catastrophe is an oncosuppressive mechanism that inhibits the proliferation and/or survival of cells that are unable to complete mitosis by inducing cell death or initiating cellular senescence. Mitotic catastrophe is recognized based on unique nuclear changes, the presence of abnormal mitotic figures and several molecular alterations. It is believed that avoiding mitotic catastrophe by genetically unstable cells promotes their unlimited growth, which can lead to cancer transformation. Therefore, the induction of mitotic catastrophe seems to be a promising strategy for the prevention and treatment of cancer. However, despite the significant role of this process, the molecular events between aberrant mitosis and cell death are still not well understood. It can be assumed that a thorough understanding of signaling pathways linking mitotic catastrophe with cell death will enable the effective use of known inducers of mitotic catastrophe in the treatment of cancer and provide new therapeutic targets. The aim of this review is to present a morphological and functional definition of mitotic catastrophe and its potential role in anticancer therapy.