Nano-enabled Coordination Platform of Bismuth Nitrate and Cisplatin Prodrug Potentiates Cancer Chemoradiotherapy via DNA Damage Enhancement

2021 ◽  
Author(s):  
Ligong Lu ◽  
Yinchu Ma ◽  
Xin-Feng Tang ◽  
Youcui Xu ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Therapeutic Efficacy ◽  
Bismuth Nitrate ◽  
Promising Strategy ◽  
Clinical Radiotherapy

The combination of chemotherapy and radiotherapy (chemoradiotherapy) is a promising strategy with extensively studied and applied clinically. Meanwhile, radiosensitizers play an important role in improving clinical radiotherapy therapeutic efficacy. There...

Thermoplastic Nanofluidic Devices for Identifying Abasic Sites in Single DNA Molecules

Lab on a Chip ◽  
2021 ◽  
Author(s):  
Steven A Soper ◽  
Swarnagowri Vaidyanathan ◽  
Franklin Uba ◽  
Bo Hu ◽  
David Kaufman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Therapeutic Efficacy ◽  
Double Strand Breaks ◽  
Dna Molecules ◽  
Strand Breaks ◽  
Single Dna Molecules ◽  
Abasic Sites ◽  
Nanofluidic Devices ◽  
Ap Sites

DNA damage can take many forms such as double-strand breaks and/or the formation of abasic (apurinic/apyrimidinic; AP) sites. The presence of AP sites can be used to determine therapeutic efficacy...

pH-responsive size-shrinkable mesoporous silica-based nanocarrier for improved tumor penetration and therapeutic efficacy

Nanoscale ◽  
2022 ◽  
Author(s):  
Yongju He ◽  
Xingyu Fan ◽  
Xiaozan Wu ◽  
Taishun Hu ◽  
Fangfang Zhou ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Mesoporous Silica ◽  
Therapeutic Efficacy ◽  
Anticancer Therapy ◽  
Major Obstacle ◽  
Drug Penetration ◽  
Ph Responsive ◽  
Tumor Penetration ◽  
Promising Strategy

Poor tumor penetration is a major obstacle to nanomedicine for achieving effective anticancer therapy. Tumor microenvironment-induced nanomedicine size shrinkage is a promising strategy to overcome the drug penetration barrier across...

scholarly journals Targeting regulatory T cells for immunotherapy in melanoma

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Lili Huang ◽  
Yeye Guo ◽  
Shujing Liu ◽  
Huaishan Wang ◽  
Jinjin Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Immune Cells ◽  
Therapeutic Efficacy ◽  
Patient Survival ◽  
Therapeutic Antibodies ◽  
Promising Strategy ◽  
Fine Tune

AbstractRegulatory T cells (Tregs) are essential in the maintenance of immunity, and they are also a key to immune suppressive microenvironment in solid tumors. Many studies have revealed the biology of Tregs in various human pathologies. Here we review recent understandings of the immunophenotypes and suppressive functions of Tregs in melanoma, including Treg recruitment and expansion in a tumor. Tregs are frequently accumulated in melanoma and the ratio of CD8+ T cells versus Tregs in the melanoma is predictive for patient survival. Hence, depletion of Tregs is a promising strategy for the enhancement of anti-melanoma immunity. Many recent studies are aimed to target Tregs in melanoma. Distinguishing Tregs from other immune cells and understanding the function of different subsets of Tregs may contribute to better therapeutic efficacy. Depletion of functional Tregs from the tumor microenvironment has been tested to induce clinically relevant immune responses against melanomas. However, the lack of Treg specific therapeutic antibodies or Treg specific depleting strategies is a big hurdle that is yet to be overcome. Additional studies to fine-tune currently available therapies and more agents that specifically and selectively target tumor infiltrating Tregs in melanoma are urgently needed.

scholarly journals Rewiring Glucose Metabolism Improves 5-FU Efficacy in Glycolytic p53-Deficient Colorectal Tumors

2021 ◽  
Author(s):  
Marlies Ludikhuize ◽  
Sira Gevers ◽  
Nguyen Nguyen ◽  
Maaike Meerlo ◽  
S. Khadijeh Shafiei Roudbari ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Glucose Metabolism ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Driver Mutations ◽  
Cycle Arrest ◽  
Promising Strategy ◽  
Clinical Models ◽  
The Warburg Effect

Abstract 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), however response rates in patients are limited to 50%. Unexpectedly, the molecular mechanisms by which 5-FU ultimately induces toxicity remain debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic intra-tumor heterogeneity, relate to the 5-FU response are ill-defined. This is largely due to a shortage of mechanistic studies in pre-clinical models able to recapitulate the key-features of CRC. Here, we analyzed the 5-FU response in human organoids genetically engineered to reproduce the different stages of CRC progression. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death. Actively proliferating cancer (stem) cells are, accordingly, efficiently targeted by 5-FU. Importantly, p53 behaves as a discriminating factor for 5-FU sensitivity, whereas p53-deficiency leads to DNA damage-induced cell death, active p53 protects from these effects through inducing cell cycle arrest. Moreover, we find that targeting the Warburg effect, by rewiring glucose metabolism, enhances 5-FU toxicity by altering the nucleotide pool and without increasing toxicity in non-transformed cells. Thus, rewiring glucose metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

scholarly journals Wee1 Inhibitor AZD1775 Combined with Cisplatin Potentiates Anticancer Activity against Gastric Cancer by Increasing DNA Damage and Cell Apoptosis

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Dongshao Chen ◽  
Xiaoting Lin ◽  
Jing Gao ◽  
Lin Shen ◽  
Zhongwu Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Cell Apoptosis ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Promising Strategy ◽  
Underlying Mechanisms ◽  
Deep Exploration

Based on the mechanisms by which Wee1 inhibitor and cisplatin played their own role, a promising strategy of Wee1 inhibitor combined with cisplatin was proposed, which was investigated in gastric cancer (GC). Either Wee1 inhibitor AZD1775 or cisplatin alone had a certain inhibitory effect on in vitro cell proliferation; however, the inhibitory effect was more significant when AZD1775 combined with cisplatin in vitro and in vivo. The underlying mechanisms unveiled that the increased DNA damage indicated by increased γH2AX protein, as well as augmented cell apoptosis indicated by upregulated proapoptotic proteins, was responsible for the significant inhibitory effect of AZD1775 plus cisplatin. Moreover, compared to any single drug, in vitro cell migration and invasion abilities were further attenuated by AZD1775 combined with cisplatin. There were suggestive results that the potentiated cytotoxicity between AZD1775 and cisplatin deserved a deep exploration in the future.

scholarly journals FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yun Huang ◽  
Hai-Liang Zhang ◽  
Zhi-Ling Li ◽  
Tian Du ◽  
Yu-Hong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Immune Responses ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Therapeutic Efficacy ◽  
Triple Negative ◽  
Sugar Moiety ◽  
Promising Strategy ◽  
Core Fucosylation

AbstractMost patients with triple negative breast cancer (TNBC) do not respond to anti-PD1/PDL1 immunotherapy, indicating the necessity to explore immune checkpoint targets. B7H3 is a highly glycosylated protein. However, the mechanisms of B7H3 glycosylation regulation and whether the sugar moiety contributes to immunosuppression are unclear. Here, we identify aberrant B7H3 glycosylation and show that N-glycosylation of B7H3 at NXT motif sites is responsible for its protein stability and immunosuppression in TNBC tumors. The fucosyltransferase FUT8 catalyzes B7H3 core fucosylation at N-glycans to maintain its high expression. Knockdown of FUT8 rescues glycosylated B7H3-mediated immunosuppressive function in TNBC cells. Abnormal B7H3 glycosylation mediated by FUT8 overexpression can be physiologically important and clinically relevant in patients with TNBC. Notably, the combination of core fucosylation inhibitor 2F-Fuc and anti-PDL1 results in enhanced therapeutic efficacy in B7H3-positive TNBC tumors. These findings suggest that targeting the FUT8-B7H3 axis might be a promising strategy for improving anti-tumor immune responses in patients with TNBC.

scholarly journals Enhancing Therapeutic Efficacy of Cisplatin by Blocking DNA Damage Repair

2016 ◽  
Vol 7 (10) ◽  
pp. 924-928 ◽  
Author(s):  
Yuwei Cong ◽  
Liangyan Wang ◽  
Zigui Wang ◽  
Shasha He ◽  
Dongfang Zhou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Therapeutic Efficacy ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals The Multifunctional Protein p62 and Its Mechanistic Roles in Cancers

2019 ◽  
Vol 19 (6) ◽  
pp. 468-478 ◽  
Author(s):  
Shunbin Ning ◽  
Ling Wang
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Chronic Inflammation ◽  
Dna Damage Response ◽  
Translational Regulation ◽  
Multifunctional Protein ◽  
Selective Autophagy ◽  
Cellular Processes ◽  
Promising Strategy ◽  
Damage Response

The multifunctional signaling hub p62 is well recognized as a ubiquitin sensor and a selective autophagy receptor. As a ubiquitin sensor, p62 promotes NFκB activation by facilitating TRAF6 ubiquitination and aggregation. As a selective autophagy receptor, p62 sorts ubiquitinated substrates including p62 itself for lysosome-mediated degradation. p62 plays crucial roles in myriad cellular processes including DNA damage response, aging/senescence, infection and immunity, chronic inflammation, and cancerogenesis, dependent on or independent of autophagy. Targeting p62-mediated autophagy may represent a promising strategy for clinical interventions of different cancers. In this review, we summarize the transcriptional and post-translational regulation of p62, and its mechanistic roles in cancers, with the emphasis on its roles in regulation of DNA damage response and its connection to the cGAS-STING-mediated antitumor immune response, which is promising for cancer vaccine design.

scholarly journals Rewiring glucose metabolism improves 5-FU efficacy in glycolytic p53-deficient colorectal tumors

2021 ◽  
Author(s):  
Marlies C. Ludikhuize ◽  
Sira Gevers ◽  
Nguyen T.B. Nguyen ◽  
Maaike Meerlo ◽  
S. Khadijeh Shafiei Roudbari ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Glucose Metabolism ◽  
Molecular Mechanisms ◽  
Cancer Metabolism ◽  
Genetically Engineered ◽  
Driver Mutations ◽  
Colorectal Tumors ◽  
Promising Strategy ◽  
The Warburg Effect

5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC). Response rates in patients are, however, limited to 50%. The molecular mechanisms by which 5-FU induces toxicity remain unclear, limiting the development of strategies to improve efficacy. How fundamental aspects, such as driver mutations and intra-tumor heterogeneity, relate to the 5-FU response is ill-defined. Here, we analyzed the 5-FU response in human organoids genetically engineered to reproduce the different stages of CRC progression. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death. Proliferating cancer (stem) cells are, accordingly, efficiently targeted by 5-FU. Importantly, p53 behaves as a discriminating factor for 5-FU sensitivity, whereas p53-deficiency leads to DNA damage-induced cell death, active p53 protects from these effects. Moreover, we find that targeting the Warburg effect, by rewiring glucose metabolism, enhances 5-FU toxicity by further altering the nucleotide pool and without increasing toxicity in healthy-non-transformed cells. Thus, targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

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