Insulin Decreases Therapeutic Efficacy in Colon Cancer Cell Line HT29 Via the Activation of the PI3K/Akt Pathway

Chen, Jiezhong; Katsifis, Andrew; Hu, Changhua; Huang, Xu‐Feng

doi:10.2174/157016311795563820

Cited by 42 publications

(32 citation statements)

References 35 publications

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“…Thus it can be speculated that patients with obesity might exhibit an impaired response to chemotherapy, particularly protocols that include targeted therapies. In addition, in some patients with obesity, increased plasma levels of insulin may further decrease therapeutic effect 88. A study of 120 patients with metastatic CRC receiving bevacizumab-based treatment (n=80) or chemotherapy alone (n=40)89 found that high BMI, and visceral and subcutaneous fat areas were significantly associated with absence of response to the bevacizumab-based treatment but not the chemotherapy group 89.…”

Section: Resultsmentioning

confidence: 99%

Obesity and colorectal cancer

Bardou

Barkun

Martel

2013

Gut

662

479

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Excess body weight, as defined by the body mass index (BMI), has been associated with several diseases and includes subjects who are overweight (BMI ≥ 25-29.9 kg/m(2)) or obese (BMI ≥ 30 kg/m(2)). Overweight and obesity constitute the fifth leading risk for overall mortality, accounting for at least 2.8 million adult deaths each year. In addition around 11% of colorectal cancer (CRC) cases have been attributed to overweight and obesity in Europe. Epidemiological data suggest that obesity is associated with a 30-70% increased risk of colon cancer in men, whereas the association is less consistent in women. Similar trends exist for colorectal adenoma, although the risk appears lower. Visceral fat, or abdominal obesity, seems to be of greater concern than subcutaneous fat obesity, and any 1 kg/m(2) increase in BMI confers additional risk (HR 1.03). Obesity might be associated with worse cancer outcomes, such as recurrence of the primary cancer or mortality. Several factors, including reduced sensitivity to antiangiogenic-therapeutic regimens, might explain these differences. Except for wound infection, obesity has no significant impact on surgical procedures. The underlying mechanisms linking obesity to CRC are still a matter of debate, but metabolic syndrome, insulin resistance and modifications in levels of adipocytokines seem to be of great importance. Other biological factors such as the gut microbiota or bile acids are emerging. Many questions still remain unanswered: should preventive strategies specifically target obese patients? Is the risk of cancer great enough to propose prophylactic bariatric surgery in certain patients with obesity?

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Section: Resultsmentioning

confidence: 99%

Obesity and colorectal cancer

Bardou

Barkun

Martel

2013

Gut

662

479

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“…Insulin has been shown to cause resistance to chemotherapy in certain colon cancer cell lines via activation of the PI3K/Akt pathway. 49,50 For the drug screening assay, hanging drops of HT-29 human colon adenocarcinoma cells were initiated and maintained on a DµF device for 48 h to allow for the formation of compact spheroids. After 48 h of culture, the medium for some spheroids was exchanged for medium containing 500 nM insulin, whereas the remaining spheroids received normal growth medium.…”

Section: Cell Spheroid Culturementioning

confidence: 99%

Digital Microfluidics for Automated Hanging Drop Cell Spheroid Culture

Aijian

Garrell

2015

SLAS Technology

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Cell spheroids are multicellular aggregates, grown in vitro, that mimic the three-dimensional morphology of physiological tissues. Although there are numerous benefits to using spheroids in cell-based assays, the adoption of spheroids in routine biomedical research has been limited, in part, by the tedious workflow associated with spheroid formation and analysis. Here we describe a digital microfluidic platform that has been developed to automate liquid-handling protocols for the formation, maintenance, and analysis of multicellular spheroids in hanging drop culture. We show that droplets of liquid can be added to and extracted from through-holes, or "wells," and fabricated in the bottom plate of a digital microfluidic device, enabling the formation and assaying of hanging drops. Using this digital microfluidic platform, spheroids of mouse mesenchymal stem cells were formed and maintained in situ for 72 h, exhibiting good viability (>90%) and size uniformity (% coefficient of variation <10% intraexperiment, <20% interexperiment). A proof-of-principle drug screen was performed on human colorectal adenocarcinoma spheroids to demonstrate the ability to recapitulate physiologically relevant phenomena such as insulin-induced drug resistance. With automatable and flexible liquid handling, and a wide range of in situ sample preparation and analysis capabilities, the digital microfluidic platform provides a viable tool for automating cell spheroid culture and analysis.

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“…Both E6 and E7 can also activate PI3K/Akt pathway, a well-known survival pathway which plays a key role in many cancers including cervical cancer [19][20][21][22][23][24][25][26] . The activation of this pathway is also associated with drug resistance to chemotherapy [27,28] . It has been demonstrated that Rb and PP2A mediate E6/E7 in activating the PI3K/Akt pathway [18,23,29] .…”

Section: Introductionmentioning

confidence: 99%

Intra-tumor injection of lentiviral-vector delivered shRNA targeting human papillomavirus E6 and E7 oncogenes reduces tumor growth in a xenograft cervical cancer model in mice

Chen¹,

McMillan

2012

JST

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Objectives: HPV is known to play a key role in the growth and maintenance of cervical cancer. Its early genes E6 and E7 can activate several intracellular signal pathways for carcinogenesis. Studies have shown that in vitro knockdown of E6 and E7 can reduce the survival ability of cervical cancer cell lines. In this study, we tested the effect of a lentiviral shRNA against E6/E7 on the tumor growth of xenografted cervical cancer HeLa cells. Methods:In vitro, the growth of HeLa cells transduced with lentiviral shRNA against E6/E7 was compared to controls. In vivo, the RAG -/-mice, which are deficient in T and B lymphocytes were used to establish the HeLa xenografted model. In the treatment group, shRNA against E6/E7 was injected into the tumor directly 30 days after HeLa cell injection when tumors have formed and the injection was repeated at day 60. A lentiviral vector without shRNA was injected in the control group.Results: HeLa cells transduced with lentiviral shRNA against E6/E7 grew slower than those with transduced with the control vector. The difference in growth rate was significant at day 4. We also observed that lentiviral shRNA significantly reduced the size of xenografted tumors compared with controls. The average tumor weight is 60% of the controls. Conclusions:Our results provide evidence that RNAi may be used for the treatment of cervical cancer by intra-tumor injection.

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Insulin Decreases Therapeutic Efficacy in Colon Cancer Cell Line HT29 Via the Activation of the PI3K/Akt Pathway

Cited by 42 publications

References 35 publications

Obesity and colorectal cancer

Obesity and colorectal cancer

Digital Microfluidics for Automated Hanging Drop Cell Spheroid Culture

Intra-tumor injection of lentiviral-vector delivered shRNA targeting human papillomavirus E6 and E7 oncogenes reduces tumor growth in a xenograft cervical cancer model in mice

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