Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Wang, Ziwen; Huang, Yujing; Zhang, Jiqiang

doi:10.2478/s11658-014-0191-7

Cited by 64 publications

(49 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Radiation therapy can reduce recurrence rates in patients by eradicating remaining cancer cells after surgical removal of tumors; however, HER2+ patients have greater chances of recurrence than HER2-patients [10,25,26]. In vitro evidence using end point assays suggests trastuzumab can sensitize HER2+ breast cancer cells to radiation through inhibition of signaling pathways involved in DNA repair mechanisms [5,27], although longitudinal data systematically evaluating the order of therapies and the associated cellular response are limited. The present study demonstrates that, in vitro, the order of trastuzumab and radiation treatment does not yield statistically signi cantly different cell responses, and their longitudinal treatment effects are additive.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Bloom

Song

Virostko

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Trastuzumab, a clinical antibody targeted to the human epidermal growth factor receptor 2 (HER2), has been shown to sensitize cells to radiation in vitro. Current studies lack longitudinal evaluation of cellular response and in vivo data is limited. The purpose of this study is to quantify the effects of combination trastuzumab and radiation therapy in vitro and in vivo over time to determine if there is a synergistic interaction. Methods: EGFP expressing BT474, SKBR3 and MDA-MB-231 cell lines were treated with 0.1 ng/ml of trastuzumab, 5 or 10 Gy of radiation, or combination treatment, and imaged using fluorescence live cell microscopy for one week. The Bliss independence model was used to quantify the effects of combination treatment. HER2+ tumor bearing mice (female NU/J) (N=34) were treated with saline, 10 mg/kg of trastuzumab, 5 or 10 Gy of radiation, or combination treatment. Tumor size was measured three times per week for four weeks via caliper measurements. Additional mice (N=13) were treated with 10 mg/kg of trastuzumab, 5 Gy of radiation, or combination treatment. Tumors were harvested at one week and evaluated with immunohistochemistry for inflammation (CD45), vascularity (CD31 and α-SMA), and hypoxia (pimonidazole). Results: Altering the order of therapies did not significantly affect BT474 cell proliferation in vitro (P>0.05). The interaction index calculations revealed additive effects of trastuzumab and radiation treatment in all three cell lines in vitro. In vivo results revealed significant differences in tumor response between mice treated with 5 and 10 Gy single agent radiation (P < 0.001); however, no difference was seen in the combination groups when trastuzumab was added to the radiation regimen (P=0.56), indicating a lower dose of radiation could be used without decreasing therapeutic efficacy. Histology results revealed increases in inflammation (CD45+) in mice receiving trastuzumab (P<0.05). Conclusions: Longitudinal evaluation of cell proliferation in vitro showed additive effects of combination therapy. In vivo results show a potential to achieve the same efficacy of treatment with reduced radiation when also administering trastuzumab. Further evaluation of tumor microenvironmental alterations during treatment could identify mechanisms of increased therapeutic efficacy in this regimen.

show abstract

Section: Discussionmentioning

confidence: 99%

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Bloom

Song

Virostko

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Therefore, the activation of the PI3K/ AKT/mTOR signaling pathway can promote tumor resistance. 31 The PI3K/AKT signaling pathway is not only involved in the regulation of tumor resistance, but also plays an important role in promoting tumor cell migration, invasion, inhibition of tumor cell apoptosis, and promotion of angiogenesis. These mechanisms can explain our experimental results.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA H19 promotes chemotherapy resistance in choriocarcinoma cells

Tan

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Choriocarcinoma (CC) is a trophoblast tumor prone to early distant organ metastases. At present, the main treatment for CC is chemotherapy, but chemotherapy resistance readily occurs and leads to treatment failure. H19 is a long noncoding RNA, and its abnormal expression has been found in various tumors, including CC. H19 is also considered to be related to the drug resistance mechanism of the same cancers. To investigate the role of H19 in drug‐resistant CC cells, the following experiments were designed. We used human CC cell line JEG‐3 to establish cell lines resistant to methotrexate and 5‐fluorouracil (JEG‐3/MTX and JEG‐3/5‐FU) and detected the expression of H19 in JEG‐3, JEG‐3/MTX, JEG‐3/5‐FU cells, JEG‐3 with MTX, and JEG‐3 with 5‐FU. We found that the expression of H19 in the JEG‐3/MTX and JEG‐3/5‐FU cells were significantly higher than that in JEG‐3 cells. JEG‐3 cells were treated with MTX or 5‐FU for and quantitative real‐time polymerase chain reaction assay revealed that H19 messenger RNA expression increased. Furthermore, after H19 was knocked out, the drug resistance index of the JEG‐3/MTX and JEG‐3/5‐FU cells decreased; the proliferation, migration, and invasion ability diminished significantly; and apoptosis increased significantly. Finally, we detected the total and phosphorylation protein expression of phosphatidylinositol‐3‐kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) in the JEG‐3/MTX and JEG‐3/5‐FU cells. The total protein of PI3K, AKT, and mTOR in the H19 knockout resistant cells showed no significant change relative to those in the H19 non‐knockout resistant cells, whereas the phosphorylated proteins of PI3K, AKT, and mTOR were significantly decreased. Phosphorylated proteins of PI3K, AKT, and mTOR in the JEG‐3/MTX and JEG‐3/5‐FU cells were significantly higher than that in JEG‐3 cells. After using inhibition of phosphorylated PI3K/AKT/mTOR, the proliferation, migration, and invasion ability of the JEG‐3/MTX and JEG‐3/5‐FU cells diminished significantly; and apoptosis increased significantly. On the basis of the above experiments, we concluded that H19 is related to the drug resistance of CC, and the knockout of H19 can reduce the drug resistance of resistant CC cells; and decrease the proliferative, migratory, and invasive ability; and increase the apoptosis. PI3K/AKT/mTOR pathway might be involved in H19‐mediated effects. H19 is expected to be a therapeutic target for the treatment of drug‐resistant chorionic carcinoma.

show abstract

“…Furthermore, Chen et al also suggested that the downregulation of miR-126 inhibited gastric tumor growth and tumor angiogenesis through activation ofAkt, mTORand Erk1/2 of VEGF-A signaling downstream genes [9, 30]. …”

Section: Discussionmentioning

confidence: 99%

The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A

Kong

Feng

et al. 2016

Cell Mol Biol Lett

View full text Add to dashboard Cite

BackgroundmiR-126 is a key regulator of oncogenic processes. It is functionally linked to cellular proliferation, survival and migration. Vascular endothelial growth factor A (VEGF-A), which is regarded as a tumorgenesis activator, could directly target miR-126 in several tumors. However, the mechanism in esophageal cancer remains unclear.Methods and resultsIn this study, the expression of miR-126 and VEGF-A were assessed in esophageal cancer tissues and esophageal cancer cell lines. We found that miR-126 has significantly lower expression in esophageal cancer tissues and esophageal cancer cell lines than in healthy tissues, while the expression of VEGF-A is high. Luciferase reporter assays were performed to investigate the relationship between VEGF-A and miR-126. We confirmed that VEGF-A is a target for miR-126. Furthermore, the proliferation of esophageal cancer cells with miR-126 overexpression and miR-126 knockdown was monitored using the MTT assay. The results showed that miR-126 could inhibit esophageal cancer cell proliferation in vitro. The effect of miR-126 was also detected in BALB/c nude mice with transplanted esophageal cancer cells. In vivo study showed that tumor growth was significantly suppressed by miR-126 overexpression.ConclusionsWe believe that restoring miR-126 levels may be a promising therapeutic approach in cases of esophageal cancer.

show abstract

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Cited by 64 publications

References 55 publications

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Long noncoding RNA H19 promotes chemotherapy resistance in choriocarcinoma cells

The crucial role of miR-126 on suppressing progression of esophageal cancer by targeting VEGF-A

Contact Info

Product

Resources

About