Therapeutic effects of protein kinase N3 small interfering RNA and doxorubicin combination therapy on liver and lung metastases

Hattori,Yoshiyuki; Kikuchi,Takuto; Nakamura,Mari; Ozaki,Kei‑Ichi; Onishi,Hiraku

doi:10.3892/ol.2017.6830

Therapeutic effects of protein kinase N3 small interfering RNA and doxorubicin combination therapy on liver and lung metastases

Authors:
- Yoshiyuki Hattori
- Takuto Kikuchi
- Mari Nakamura
- Kei‑Ichi Ozaki
- Hiraku Onishi
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Affiliations: Department of Drug Delivery Research, Hoshi University, Tokyo 142‑8501, Japan, Education and Research Center for Fundamental Pharmaceutical Sciences, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569‑1094, Japan
Published online on: August 25, 2017 https://doi.org/10.3892/ol.2017.6830
Pages: 5157-5166
Copyright: © Hattori et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been reported that suppression of protein kinase N3 (PKN3) expression in vascular and lymphatic endothelial cells results in the inhibition of tumor progression and lymph node metastasis formation. The present study investigated whether combination therapy of small interfering RNA (siRNA) against PKN3 and doxorubicin (DXR) could increase therapeutic efficacy against liver and lung metastases. In vitro transfection of PKN3 siRNA into PKN3‑positive MDA‑MB‑231, LLC, and Colon 26 cells and PKN3‑negative MCF‑7 cells did not inhibit cell growth and did not increase sensitivity to DXR. However, following in vivo treatment, PKN3 siRNA suppressed the growth of liver MDA‑MB‑231 and lung LLC and MCF‑7 metastases, although combination therapy with DXR did not increase the therapeutic efficacy. By contrast, in liver MCF‑7 metastases, PKN3 siRNA or DXR alone did not exhibit significant inhibition of tumor growth, but their combination significantly improved therapeutic efficacy. Treatment of liver MDA‑MB‑231 metastases with PKN3 siRNA induced a change in vasculature structure via suppression of PKN3 mRNA expression. PKN3 siRNA may induce antitumor effects in lung and liver metastases by suppression of PKN3 expression in stroma cells, such as endothelial cells. From these findings, PKN3 siRNA alone or in combination with DXR may reduce the tumor growth of liver and lung metastases regardless of PKN3 expression in tumor cells.

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