A Brief look at antitumor effects of doxycycline in the treatment of colorectal cancer and combination therapies

2021 ◽  
pp. 174593
Author(s):  
Kimia Ghasemi ◽  
Kosar Ghasemi
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapies ◽  
Antitumor Effects

scholarly journals PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002844
Author(s):  
Alexander Stein ◽  
Donjete Simnica ◽  
Christoph Schultheiß ◽  
Rebekka Scholz ◽  
Joseph Tintelnot ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Multispectral Imaging ◽  
Standard Treatment ◽  
Immune Escape ◽  
Killer Cell ◽  
Cell Killing ◽  
Antitumor Effects ◽  
High Affinity

BackgroundIn patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration.MethodsWe treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing.ResultsCirculating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion.ConclusionThe addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation.Trial registration numberNCT03174405.

scholarly journals Remodeling of Cancer-Specific Metabolism under Hypoxia with Lactate Calcium Salt in Human Colorectal Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1518
Author(s):  
Keun-Yeong Jeong ◽  
Jae-Jun Sim ◽  
Min Hee Park ◽  
Hwan Mook Kim
Keyword(s):  
Colorectal Cancer ◽  
Intracellular Calcium ◽  
Cancer Cells ◽  
Calcium Salt ◽  
Lactate Production ◽  
Tca Cycle ◽  
Anaerobic Glycolysis ◽  
Human Colorectal Cancer ◽  
Antitumor Effects ◽  
Enzymatic Activation

Hypoxic cancer cells meet their growing energy requirements by upregulating glycolysis, resulting in increased glucose consumption and lactate production. Herein, we used a unique approach to change in anaerobic glycolysis of cancer cells by lactate calcium salt (CaLac). Human colorectal cancer (CRC) cells were used for the study. Intracellular calcium and lactate influx was confirmed following 2.5 mM CaLac treatment. The enzymatic activation of lactate dehydrogenase B (LDHB) and pyruvate dehydrogenase (PDH) through substrate reaction of CaLac was investigated. Changes in the intermediates of the tricarboxylic acid (TCA) cycle were confirmed. The cell viability assay, tube formation, and wound-healing assay were performed as well as the confirmation of the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). In vivo antitumor effects were evaluated using heterotopic and metastatic xenograft animal models with 20 mg/kg CaLac administration. Intracellular calcium and lactate levels were increased following CaLac treatment in CRC cells under hypoxia. Then, enzymatic activation of LDHB and PDH were increased. Upon PDH knockdown, α-ketoglutarate levels were similar between CaLac-treated and untreated cells, indicating that TCA cycle restoration was dependent on CaLac-mediated LDHB and PDH reactivation. CaLac-mediated remodeling of cancer-specific anaerobic glycolysis induced destabilization of HIF-1α and a decrease in VEGF expression, leading to the inhibition of the migration of CRC cells. The significant inhibition of CRC growth and liver metastasis by CaLac administration was confirmed. Our study highlights the potential utility of CaLac supplementation in CRC patients who display reduced therapeutic responses to conventional modes owing to the hypoxic tumor microenvironment.

scholarly journals Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Li ◽  
Yan Wang ◽  
Yueqing Gong ◽  
Tengrui Zhang ◽  
Jiaqi Huang ◽  
...  
Keyword(s):  
Treatment Modalities ◽  
Preclinical Studies ◽  
Combination Therapies ◽  
Tumor Treatment ◽  
Antitumor Effects ◽  
Therapeutic Modalities ◽  
Combination Strategies ◽  
Anti Cancer ◽  
Underlying Mechanisms ◽  
The Individual

AbstractEnhancer of zeste homolog 2 inhibitors (EZH2i) have garnered increased attention owing to their anticancer activity by targeting EZH2, a well-known cancer-promoting factor. However, some lymphomas are resistant to EZH2i, and EZH2i treatment alone is ineffective in case of EZH2-overexpressing solid tumors. The anti-cancer efficacy of EZH2i may be improved through safe and effective combinations of these drugs with other treatment modalities. Preclinical evidence indicates that combining EZH2i with other therapies, such as immunotherapy, chemotherapy, targeted therapy, and endocrine therapy, has complementary or synergistic antitumor effects. Therefore, elucidating the underlying mechanisms of the individual constituents of the combination therapies is fundamental for their clinical application. In this review, we have summarized notable clinical trials and preclinical studies using EZH2i, their progress, and combinations of EZH2i with different therapeutic modalities, aiming to provide new insights for tumor treatment.

scholarly journals The Role of Dynamic ctDNA Monitoring During Combination Therapies of BRAF V600E-Mutated Metastatic Colorectal Cancer: A Case Report

2020 ◽  
Vol Volume 13 ◽  
pp. 11849-11853
Author(s):  
Zhan Wang ◽  
Chen-Yang Ye ◽  
Wen-Li Zhou ◽  
Miao-Miao Wang ◽  
Wei-Ping Dai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Report ◽  
Metastatic Colorectal Cancer ◽  
Braf V600e ◽  
Combination Therapies

scholarly journals Combination of oncolytic adenovirus and luteolin exerts synergistic antitumor effects in colorectal cancer cells and a mouse model

2017 ◽  
Vol 16 (6) ◽  
pp. 9375-9382 ◽  
Author(s):  
Boduan Xiao ◽  
Yun Qin ◽  
Chang Ying ◽  
Buyun Ma ◽  
Binrong Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Oncolytic Adenovirus ◽  
Antitumor Effects ◽  
Colorectal Cancer Cells

Antitumor effects of a covalent cyclin-dependent kinase 7 inhibitor in colorectal cancer

2019 ◽  
Vol 30 (5) ◽  
pp. 466-474 ◽  
Author(s):  
Jian Wang ◽  
Zhenyu Li ◽  
Hong Mei ◽  
Dejun Zhang ◽  
Gang Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cyclin Dependent Kinase ◽  
Antitumor Effects

scholarly journals Helicteric Acid, Oleanic Acid, and Betulinic Acid, Three Triterpenes fromHelicteres angustifoliaL., Inhibit Proliferation and Induce Apoptosis in HT-29 Colorectal Cancer Cells via Suppressing NF-κB and STAT3 Signaling

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Dan Su ◽  
Yu-qiao Gao ◽  
Wei-bo Dai ◽  
Ying Hu ◽  
Yan-fen Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Betulinic Acid ◽  
Biological Activities ◽  
Colorectal Tumor ◽  
Antitumor Effects ◽  
Chinese Medicinal Herb ◽  
Stat3 Signaling ◽  
Colorectal Cancer Cells ◽  
Ht 29

Colorectal cancer (CRC) is one of the most common malignancies and most frequent cause of cancer death worldwide. The activation of both NF-κB and STAT3 signaling and the crosstalk between them play an important role in colorectal tumor.Helicteres angustifoliaL. is a type of commonly used Chinese medicinal herb and possesses a wide variety of biological activities. In the present study, we investigate the effects of three triterpenes fromH. angustifolia(HT) such as helicteric acid (HA), oleanic acid (OA), and betulinic acid (BA), on inhibiting CRC progression. Our results showed that HT extracts could decrease proliferation and induce apoptosis in HT-29 colorectal cancer cells. Moreover, HT extracts could suppress LPS-triggered phosphorylation of IKK, IκB, and NF-κB, attenuate IL-6-induced phosphorylation of JAK2 and STAT3, and suppress the expression of c-Myc, cyclin-D1, and BCL-xL, the downstream gene targets of NF-κB and STAT3. Therefore, HT extracts showed potent therapeutic and antitumor effects on CRC via inhibiting NF-κB and STAT3 signaling.

scholarly journals Ginsenoside Rg3 Sensitizes Colorectal Cancer to Radiotherapy through Downregulation of Proliferative and Angiogenic Biomarkers

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Taiguo Liu ◽  
Lina Duo ◽  
Ping Duan
Keyword(s):  
Quality Of Life ◽  
Colorectal Cancer ◽  
Gene Products ◽  
Ginsenoside Rg3 ◽  
Mobility Shift ◽  
Antitumor Effects ◽  
Fractionated Radiotherapy ◽  
Mobility Shift Assay

Background. Radiation therapy is an important mode of colorectal cancer treatment. However, most people die of local recurrence after tumors become resistant to radiotherapy, and little progress has been made in treating radiotherapy-resistant colorectal cancer. Hence, novel agents that are nontoxic and can sensitize colorectal cancer to radiotherapy are urgently needed. Ginsenoside Rg3, a saponin extracted from ginseng, shows cytotoxicity against a variety of cancer cells through suppression of pathways linked to oncogenesis, including cell survival, proliferation, invasion, and angiogenesis. In this article, we investigated whether Rg3 can sensitize colorectal cancer to radiation in vivo. Methods and Materials. We established CT-26 xenografts in BALB/c mice and treated them with vehicle, Rg3, radiation, and combined Rg3 + radiation. Mouse quality of life, survival, tumor volumes, and inhibitive rates were estimated. NF-κB activation was ascertained using electrophoretic mobility shift assay and immunohistochemistry. We also tested for markers of proliferation, angiogenesis, and invasion using immunohistochemistry and Western blot analysis. Results. Rg3 significantly enhanced the efficacy of fractionated radiotherapy by improving the quality of life of mice. Moreover, tumors from mice xenografted with CT-26 cells and treated with combined Rg3 + radiotherapy showed significantly lower tumor volumes (P<0.01 versus controls; P<0.05 versus radiation alone), NF-κB activation, and expression of NF-κB-regulated gene products (cyclin D1, survivin, cyclooxygenase-2 (COX-2), and vascular endothelial growth factor (VEGF)) compared with controls. The combination treatment was also effective in suppressing angiogenesis, as indicated by lower CD31+ microvessel density compared with controls (P<0.05). Conclusion. Our results suggest that Rg3 enhances the antitumor effects of radiotherapy for colorectal cancer by suppressing NF-κB and NF-κB-regulated gene products, leading to inhibition of tumors and prolongation of the lifespan of CT-26 xenograft BALB/c mice.

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