Oncotarget

Research Papers:

Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells

Pengfei Jiang _, Peiying Zhang, Rajesh Mukthavaram, Natsuko Nomura, Sandeep C. Pingle, Dayu Teng, Shu Chien, Fang Guo and Santosh Kesari

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Oncotarget. 2016; 7:57932-57942. https://doi.org/10.18632/oncotarget.10773

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Abstract

Pengfei Jiang1,*, Peiying Zhang2,*, Rajesh Mukthavaram1, Natsuko Nomura1, Sandeep C. Pingle1, Dayu Teng3,6, Shu Chien3,6, Fang Guo4, Santosh Kesari5

1Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA

2Department of Cardiology, Xuzhou Central Hospital, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou Clinical School of Xuzhou Medical College, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, Xuzhou, Jiangsu Province 221009, China

3Department of Bioengineering, UC San Diego, La Jolla, CA 92093, USA

4Key Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China

5Department of Translational Neuro-Oncology and Neurotherapeutics, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, CA 90404, USA

6Institute of Engineering in Medicine, UC San Diego, La Jolla, CA 92093, USA

*Co-first authors

Correspondence to:

Pengfei Jiang, email: [email protected]

Santosh Kesari, email: [email protected]

Keywords: glioblastoma, bisphosphonates, zoledronic acid, cancer therapy, autophagy

Received: August 14, 2015     Accepted: July 05, 2016     Published: July 22, 2016

ABSTRACT

Zoledronic acid, a potent nitrogen-containing bisphosphonate (NBP), has been extensively used to limit bone turnover in a various diseases including tumors. Recent clinical studies have demonstrated direct anti-cancer effects of zoledronic acid, in addition to its clinical benefits for skeletal-related events. Here we investigated the effects of 4 clinically available NBPs on human tumor cell proliferation. Our data demonstrate a potent anti-proliferative effect of zoledronic acid against glioblastoma (GBM) cell lines, breast cancer cells and GBM patient-derived lines. Zoledronic acid also effectively inhibited GBM tumor growth in xenograft mouse models. Zoledronic acid strongly stimulated autophagy but not apoptotic signals in all tested cells. Only one intermediate product of cholesterols synthesis pathway, geranylgeranyl diphosphate (GGPP) rescued cells from the cytotoxic effects of zoledronic acid. To further investigate the effect of GGPP, we knocked down RABGGTA, which encodes a subunit of the Rabgeranylgeranyltransferase protein. This knockdown induced an effect similar to zoledronic acid in cancer cell lines. These data are promising and suggested a potential for zoledronic acid as an anti-cancer agent, through its ablation of the function of Rab proteins.


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