Targeted Therapy of Colorectal Cancer

Seeber, Andreas; Gastl, Günther

doi:10.1159/000453027

Cited by 41 publications

(41 citation statements)

References 45 publications

(45 reference statements)

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“…Regorafenib is also a biologic agent, an oral tyrosine kinase inhibitor that has multiple targets, including VEGF receptors 1, 2, and 3. It was approved for chemotherapy-refractory mCRC in 2013 [15][16][17][18][19][20].…”

Section: Metastatic Diseasementioning

confidence: 99%

Colorectal cancer treatment: An introduction

António¹,

Fröbe²,

Đaković³

et al. 2017

Rad Hrvatske akademije znanosti i umjetnosti

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SummaryColorectal cancer (CRC) is one of the most frequent type of cancers, and also one of the most frequent causes of death among cancer patients worldwide. Approximately 25% of newly diagnosed patients with CRC have already developed metastases, and 50% of all CRC patients will develop metastases over time as the disease progresses. Active oncological treatment of patients having metastatic CRC nowadays includes fluoropyrimidines in combination with irinotecan and/or oxaliplatin ± monoclonal antibodies (mAbs). Development and introduction of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF; bevacizumab) and the epidermal growth factor receptor (EGFR; cetuximab, panitumumab) in treatment algorithms for patients with wild-type K/N-RAS have significantly improved median overall survival (OS) of patients with metastatic colorectal cancer.Clinical experience supported by various patohistological and molecular biology data indicates that CRC is a heterogeneous disease. The novel approach to treatment decisions should be patient personalized, i.e. such decisions should be tailored according to patient clinical (age, performance status, comorbidities) and molecular (pharmacogenetic) characteristics, tumor disease stage, tumor location and tumor molecular characteristics and patient preferences. Treatment decision for patients with metastatic CRC must be evidence based. The role of the multidisciplinary team in recommendation preparation is unavoidable.

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Section: Metastatic Diseasementioning

confidence: 99%

Colorectal cancer treatment: An introduction

António¹,

Fröbe²,

Đaković³

et al. 2017

Rad Hrvatske akademije znanosti i umjetnosti

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“…Several successful cases treated with this therapy have been reported so far; for example, bevacizumab has been used for VEGF inhibition and ramucirumab for the inhibition of its type 2 receptor . These monoclonal antibodies can control the growth of cancers, such as advanced colorectal, gastric, lung, ovarian, and brain malignancies. Small molecules, such as sorafenib and sunitinib, which show multiple kinase inhibitory activities, can suppress VEGF receptors (VEGFR) and inhibit tumor angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Curcumin analog, GO‐Y078, overcomes resistance to tumor angiogenesis inhibitors

Shimazu

Inoue

Sugiyama³

et al. 2018

Cancer Science

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Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO‐Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO‐Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC‐R). GO‐Y078 inhibited the growth and mobility of HUVEC‐R at 0.75 μmol/L concentration. Expression analyses by microarray and RT‐PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO‐Y078. In a knockdown experiment using Si‐oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO‐Y078. Knockdown of FN1 resulted in the suppression of HUVEC‐R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO‐Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO‐Y078.

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Section: Introductionmentioning

confidence: 99%

“…Therapeutic methods utilizing molecular targets to alter cancer cell properties possess more powerful antitumor functions and fewer toxic effects towards healthy cells (2). As a result, small molecule target therapeutics for cancer has been the subject of numerous investigations (2). The heat shock protein (hsp) family, particularly hsp90, is associated with the stability of a number of key oncogenic target proteins, including receptor and non-receptor tyrosine kinases, and is therefore a promising molecular target for cancer treatment (3).…”

Section: Introductionmentioning

confidence: 99%

Effects of 17-allylamino-17-demethoxygeldanamycin on the induction of apoptosis and cell cycle arrest in HCT-116 cells

et al. 2017

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The present study investigated the effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on apoptosis and the cell cycle of the HCT-116 human colon carcinoma cell line, with the aim of elucidating their underlying mechanisms. MTT was used to examine the inhibitory effects of 17-AAG on the proliferation of HCT-116 cells at various time points and doses. The cells were stained with Annexin V-fluorescein isothiocyanate/propidium iodide and evaluated by flow cytometry. The expression of signal transducer and activator of transcription (STAT)3, cyclin D1, cytochrome c (cyt-c), caspase 9 and caspase 3 at the mRNA and protein level was determined using reverse transcription-polymerase chain reaction and western blotting. Treatment with 17-AAG at a concentration of 1.25–20 mg/l for 24 and 48 h significantly inhibited the proliferation of HCT-116 cells in a time-dependent and concentration-dependent manner. Treatment with 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly induced apoptosis and cell cycle arrest in HCT-116 cells. Exposure to 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly downregulated the mRNA and protein expression of STAT3 and cyclin D1, but upregulated cyt-c, caspase 9 and caspase 3 in a concentration-dependent manner in HCT-116 cells. Therefore 17-AAG is able to inhibit cell proliferation, inducing apoptosis and G1 stage cell cycle arrest by downregulating the expression of cyclin D1, and promoting the mitochondria apoptosis by downregulating STAT3 in HCT-116 cells.

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Targeted Therapy of Colorectal Cancer

Cited by 41 publications

References 45 publications

Colorectal cancer treatment: An introduction

Colorectal cancer treatment: An introduction

Curcumin analog, GO‐Y078, overcomes resistance to tumor angiogenesis inhibitors

Effects of 17-allylamino-17-demethoxygeldanamycin on the induction of apoptosis and cell cycle arrest in HCT-116 cells

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