DOI: 10.25934/pr00004919
title: Effect of digoxin on survival outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors 

description: Renal cell cancer (RCC) is by far the most common type of kidney cancer in adults. Approximately 9 out of 10 kidney cancers are RCC. The incidence of RCC among men is 1.6 to 2.0 times higher than that in women, and men account for nearly 70% of all deaths from RCC1. Almost 70% of renal cell cancer is of the clear cell subtype, and 25-30% of people have metastatic spread by the time they are diagnosed with renal cell cancer (www.cancer.org). In The Netherlands, 2343 patients were diagnosed with renal cell cancer in 2015. 

During the past two decades, the treatment of metastatic RCC (mRCC) has underwent a major evolution. Treatment strategies have changed from interleukin-2 and interferon-alpha to targeted therapy including tyrosine kinase inhibitors (TKIs) such as sunitinib, sorafenib, pazopanib and axitinib; mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus and everolimus; and the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab. As a result, the five-year-survival rate for patients with stage I-IV RCC has improved from 51% in 1989-1993 to 63% in 2008-2012. (http://www.cijfersoverkanker.nl/). However, for patients with metastatic renal cell cancer (mRCC), the five-year-survival rate remains low at ~8-25%.

Internal hypoxia is a common characteristic of solid tumors including renal cell carcinoma. Hypoxia-inducible factors (HIFs) play an essential role in tumor adaption to low oxygen concentration or hypoxia by up-regulating angiogenetic proteins such as VEGF, resulting in angiogenesis, tumor growth, progression and metastatic spread2. There are three different forms of HIF (HIF1, HIF2 and HIF3) and all are composed of O2-regulated α subunit and generally expressed β subunit. Current data suggests that HIF1 plays a central role in response to oxygen3. It was reported that HIF1 is overexpressed in most human malignancies including colorectal, gastric and RCC, and the clear cell RCC subtype showed the highest HIF expression levels4. Chen et al.5 reported in 2005 that the high expression of HIF1α was significantly correlated with larger tumor size and higher incidence of recurrence and distant metastasis of gastrointestinal stromal tumor.  Besides, a recent study suggested that higher HIF1α expression might be associated with worse progression-free survival of patients treated with sunitinib6. Taken together, HIF1 expression plays an important role in tumor progression and anti-angiogenesis treatment outcome.  
Direct inhibition of HIF activity presents a promising target for the development of new anti-cancer drugs. Currently, over 40 HIF-inhibitors have been identified, including several commonly available drug classes such as mTOR-inhibitors and cardiacglycosides7. These drugs present attractive candidates to test as anticancer drugs as they are used extensively and have a well-established safety profile. Digoxin, a commonly used drug to treat atrial fibrillation, has been shown to inhibit HIF activity (Figure 1). In-vitro experiments in TK-10 renal adenocarcinoma cell lines have shown that digoxin can induce apoptosis (IC50 14.6±2.2nM)8.  Moreover, in mice receiving digoxin, Zhang et al.7 observed not only the significant inhibition of tumor growth but also the decreased expression of HIF1α protein and mRNA for VEGF. Recently, Kolf et al.9 reported that treatment with digoxin and paclitaxel decreased tumor size by 30% more compared to treatment with paclitaxel alone in mice with breast cancer. The aforementioned findings present evidence from cell lines and mice model, indicating the antitumor activity of digoxin. In addition, data indicating similar effects in cancer patients are emerging. Menger et al.10 summarized the progress of clinical studies which evaluated or are evaluating the safety and efficacy of cardiac glycosides including digoxin for oncological indications. It was reported that carcinoma patients co-treated with digoxin showed a significantly increased overall survival compared with matched patients without concomitant digoxin11. The 5-year survival rate for patients received digoxin was 65% (56-73%), whereas patients without co-treated with digoxin showed a 52% (45-58%) survival at 5 years11.

Based on this information, we hypothesize that mRCC patients treated by TKIs concomitant with digoxin could have an improved survival outcome compared with those only treated by TKIs.