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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2013

01-10-2013 | Original Article

Lidamycin up-regulates the expression of thymidine phosphorylase and enhances the effects of capecitabine on the growth and pulmonary metastases of murine breast carcinoma

Authors: Sheng-hua Zhang, Hao Zhang, Hong-wei He, Liang Li, Xing-qi Li, Yi-ping Zhang, Rong-guang Shao

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2013

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Abstract

Purpose

Capecitabine (CAP), a prodrug, needs to be converted to 5-fluorouracil by several key enzymes, including thymidine phosphorylase (TP). To improve the therapeutic index, potentiation of antitumor activity of CAP is required. In this study, we explored whether lidamycin (LDM), an enediyne anticancer antibiotic, can induce synergistic antitumor effects in combination with CAP in murine breast cancer in vitro and in vivo.

Methods

Using MTT, cell migration and invasion, siRNA knockdown, and Western blot assays, the in vitro synergistic effects of LDM plus CAP on 4T1LUC cells were evaluated, and the mechanism of this synergy was explored. For in vivo model of orthotopic implantation model of 4T1LUC cells, optical molecular imaging system was utilized to evaluate the growth of primary tumor and metastasis. To further understand the mechanism of action of the LDM/CAP combination, immunohistochemistry analysis was carried out to detect thymidine phosphorylase induction and ERK signaling.

Results

As determined by MTT and transwell assay, LDM enhanced the inhibitory effects of CAP on cancer cell proliferation, migration, and invasion. Western blot showed that this synergistic effect was attributed to the up-regulated expression of TP induced by LDM. Knocking down TP impaired the synergistic anti-proliferative effect of LDM and CAP. Furthermore, our data suggested that LDM-induced up-regulation of TP both in vitro and in vivo is associated with ERK activation, because the inhibition of ERK activity by ERK inhibitor U0126 abrogated LDM-induced TP up-regulation. In animal models, LDM plus CAP potently inhibited primary tumor growth as well as lung metastasis compared with control or single-agent-treated group.

Conclusions

LDM can potentiate the antitumor effects of CAP on breast cancer line. The synergistic effects suggest that the combination of LDM and CAP is an innovative antitumor strategy for breast cancer therapy.
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Metadata
Title
Lidamycin up-regulates the expression of thymidine phosphorylase and enhances the effects of capecitabine on the growth and pulmonary metastases of murine breast carcinoma
Authors
Sheng-hua Zhang
Hao Zhang
Hong-wei He
Liang Li
Xing-qi Li
Yi-ping Zhang
Rong-guang Shao
Publication date
01-10-2013
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-013-2253-3

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