Complementary treatment of siTERT for improving the antitumor effect of TERT-specific I-131 therapy

Abstract

Sodium iodide symporter (NIS)-based radionuclide therapy provides an effective means of treating malignant tumors. However, it is sometimes inadequate because of limited effects on radio-resistant tumors, and thus, combination therapies with other therapeutic options have been requested to enhance its efficacy. Human telomerase reverse transcriptase (hTERT) has been reported to be involved in the progression of most cancers and also been viewed as a good candidate for targeting tumor. Application of TERTspecific radionuclide therapies using NIS gene transfer have been reported to treat TERT-positive tumors, but this approach only demonstrated tumor regression rather than eradication. As inhibiting TERT expression by introducing the hTERT-specific shRNA (siTERT) has been suggested as a therapeutic option, we investigated the complementary role of siTERT treatment after the TERTspecific I-131 therapy and its possibility as a novel anticancer therapeutic strategy. Retroviruses containing TERT promoter/NIS for TERT specific Radionuclide therapy and siTERT for TERT targeting antisense therapy were produced. Hep3B cells expressing TERT specific NIS (Hep3B-TERT/NIS) were xenografted into nude mouse and visualized with micro-SPECT/CT for monitoring NIS activity. The levels of hTERT mRNA, protein and its activity were confirmed by RT-PCR, Western blotting and Telomerase repeat amplification protocol assay. Cell proliferation was monitored by MTT assay and induced apoptosis was confirmed by Annexin-V-PI staining. Therapeutic effects of I-131 and/or siTERT were evaluated by clonogenic assay and mouse tumor model. Reduction of hTERT mRNA, protein and TERT activity by siTERT were observed in Hep3B-TERT/NIS cells. The viabilities of the infected cells were significantly decreased to 50% versus siScramble treated controls. The early apoptotic cell population was increased by siTERT. The survival rates of cells treated with siTERT or I-131 alone were 72.4 ± 7.6% and 56.2 ± 5.2%, respectively. However, the survival rate of cells treated with I-131 and siTERT were decreased to 22.1 ± 2.8%. From mouse xenograft model, we also found that the siTERT gene therapy showed synergism to the radioiodine therapy for reducing tumor growth in vivo. Our Results suggested that complementary siTERT gene therapy offers a novel strategy of cancer therapy to improve the therapeutic efficacy of TERT-specific I-131.

Silencing of the hTERT Gene by shRNA Inhibits Colon Cancer SW480 Cell Growth In Vitro and In Vivo

“…Formulating the siRNA with bioreducible cationic polymers, for example, shows substantial promise [45], [33], as does packaging in adenovirus [31]. Combining siRNA against hTERT with other therapies, such as radiation treatment [46], may also be appropriate. In this way, the present study opens the door wider for applied mechanistic and pharmacologic studies of hTERT-based RNAi in colon cancer.…”

Imaging & Machine Learning Techniques Used for Early Identification of Cancer in Breast Mammogram

“…This process is named as metastasis. Generally, breast cancer is developed in the ducts or in the lobes which are called lobular cancer [16]. Benign tumors are abnormal growth but do not spread uncontrollably.…”

“…Histogram features and intensity features followers fundamental statistics based on its independent pixel value, whereas GLCM follows second-order statistics based on its neighboring pixels. Kim et al [35] developed a new analysis technique called surrounding region dependence method (SRDM), for identifying cluster micro calcification in digitized x-ray. A back propagation neural network with its three layers is used to classify masses in the mammogram.…”