Effect of combination therapy of siRNA targeting growth hormone receptor and 5-fluorouracil in hepatic metastasis of colon cancer

Abstract

The aim of this study was to investigate the effects of small interfering RNA (siRNA) targeting human growth hormone receptor (hGHR) combined with 5-fluorouracil (5-FU) on the hepatic metastasis of colon cancer. The animal model of liver metastases using human SW480 colon cancer cells was established on BALB/c mice and the siRNA interfering plasmid targeting hGHR gene was constructed. The tumor-bearing mice were randomly divided into the saline control, plasmid, growth hormone (GH), 5-FU, 5-FU+plasmid and 5-FU+plasmid+GH groups. The liver metastasis in each group was observed. All the animals showed liver metastases and using siRNA-interfering plasmid treatment the incidence of liver metastases was significantly reduced in the tumor groups compared to the saline or GH group. The combined treatment of interfering plasmid and 5-FU slightly decreased the incidence of liver metastases in the tumor groups compared to the plasmid alone or 5-FU alone treatment, although the findings were not statistically significant. On the basis of the combination of interfering plasmid and 5-FU, the additional GH did not increase the incidence of liver metastases (P>0.05), but improved the weight loss of the mice (P<0.05) induced by the inhibition of GHR and toxicity of 5-FU. The present results showed that siRNA targeting hGHR is able to reduce the incidence of liver metastases of human SW480 colon cancer cells in mice. Thus, GHR may be important in tumor metastasis.

Cancer and the metastatic substrate

“…Another study used an animal model to examine the combined effect of SiARN targeting the hGHR growth hormone receptor and 5-fluorouracil on colon cancer metastases. The results of that study showed that this combination reduced the incidence of liver metastasis in colon cancer [174]. A study of 46,027 patients examined metastatic distribution patterns in colon and rectal cancer.…”

Oral siRNA Delivery to Treat Colorectal Liver Metastases

“…As a potential strategy to overcome the side effects of FOLFOX or FOLFIRI, application of RNAi has been suggested to treat CLM. Indeed, several studies have demonstrated prevention of micrometastases and metastatic growth of CRC in the liver. − Although the results showed promising potential for treatment of CLM, translation of RNAi-based therapies toward clinical settings poses challenges, including intrinsic poor serum stability and nonspecific uptake into biological systems, suggesting a need for the development of efficient delivery systems …”

Identification of growth hormone receptor as a relevant target for precision medicine in low‐EGFR expressing glioblastoma

“…This compound was shown to be efficient in various tumour types 62 , 63 , 64 , 65 , 66 and to potentiate chemotherapy efficacy. 67 However, its poor passage across the blood–brain barrier 68 predicts low efficacy for GBM treatment. Other GHR‐targeted compounds currently in clinical development such as antisense oligonucleotides 69 could constitute a promising approach, although the capacity of such molecules to reach the brain remains to be assessed.…”

“…Pegvisomant is an efficient PEGylated GH core‐based peptide antagonist currently used in the clinics to counteract excess of GHR signalling in acromegalic patients. This compound was shown to be efficient in various tumour types 62–66 and to potentiate chemotherapy efficacy 67 . However, its poor passage across the blood–brain barrier 68 predicts low efficacy for GBM treatment.…”