Abstract

BackgroundThis study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug.MethodsThe orthotopic nude mice model of highly metastatic HCC was established and the animals were randomized and treated with PDOX, DOX and saline, respectively. Hematology, biochemistry and tumor markers were studied. At autopsy, liver tumor weight and size, ascites, abdominal lymph nodes metastases, experimental peritoneal carcinomatosis index (ePCI), and tumor-host body weight ratio were investigated. Immunohistochemical studies and western blotting were done to investigate key molecules involved in the mechanism of action.ResultsCompared with Control, both PDOX and DOX could similarly and significantly reduce liver tumor weight and tumor volume by over 40%, ePCI values, retroperitoneal lymph node metastases and lung metastases and serum AFP levels (P < 0.05). The PDOX group had significantly higher WBC than the DOX group (P < 0.05), and higher PLT than Control (P < 0.05). Serum BUN and Cr levels were lower in the PDOX group than DOX and Control groups (P < 0.05). Compared with Control, DOX increased CK and CK-MB; while PDOX decreased CK compared with DOX (P < 0.05). Multiple spotty degenerative changes of the myocardium were observed in DOX-treated mice, but not in the Control and PDOX groups. PDOX could significantly reduce the Ki-67 positive rate of tumor cells, compared with DOX and Control groups. PDOX produced the effects at least via the ERK pathway.ConclusionCompared with DOX, PDOX may have better anti-metastatic efficacy and reduced side effects especially cardio-toxicities in this HCC model.

Highlights

  • This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug

  • In our previous animal model study, we investigated the activities and side effects of PDOX to treat peritoneal carcinomatosis (PC) from gastric cancer, which suggests that PDOX might be a promising new drug against cancer invasion [15]

  • PDOX had better effects on general status and similar inhibitory effects on liver tumor growth and loco-regional metastases After tumor inoculation into the liver, the animals in the DOX and PDOX groups showed slight and progressive body weight decreases till the study endpoint

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Summary

Introduction

This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug. Hepatocellular carcinoma (HCC) is the fifth most frequent malignant tumors, and the third leading cause of cancer-related mortality in the world [1]. Increasing evidence supports the role of cathepsin B (Cat B) in tumor invasion and metastasis [7,8,9], including HCC progression [10]. Cat B expression is increased in many cancers at the mRNA, protein and activity levels, and closely related to invasive behavior of cancer [11].

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