Abstract
Background: Currently, most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria caused by anti-angiogenic drugs (AADs) according to diabetic nephropathy guidelines or expert recommendations. However, the efficacy ACEIs and potential cancer promoting effect are controversial. This study aimed at confirming whether ACEIs are beneficial in anti-angiogenesis therapy for hepatocellular carcinoma. Methods: In clinic, we observed the impact of ACEIs on AADs during the treatment of hepatocellular carcinoma. Next, we established different tumor-bearing mouse models to confirm that whether ACEIs have any effect on the anti-cancer efficacy and proteinuria side effects of AADs. Further, we confirmed the relevant mechanism in vivo. Findings: Our clinical data have shown that some hepatocellular carcinoma (HCC) patients experienced tumor progression by ACEIs administration for the treatment of hypertension or proteinuria caused by AADs. We have confirmed that in different tumor-bearing mouse models, ACEIs did not delay the appearance of proteinuria or alleviate proteinuria caused by AADs but compromised the anticancer efficacy of AADs. This effect is unrelated to a change in the VEGF signaling pathway. Our data showed that the combination of ACEIs and AADs flared the production of kidney-derived erythropoietin (EPO). In turn, EPO compromises the anti-angiogenic effects of AADs and decreases antitumor activity. Interpretation: For the treatment of proteinuria caused by AADs, ACEIs have no efficacy but promote drug resistance. Kidney-derived EPO is mainly responsible for ACEIs induced anti-angiogenesis resistance. Funding Statement: This study was supported by the National Natural Science Foundation of China (No. 81672884) and the National Science and Technology Major Project of China (No. 2017ZX10203207-004-005). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: All human studies were approved by the Clinical Research Ethics Committee of Tianjin Medical University Cancer Institute. All animal experiments were carried out in accordance with a protocol approved by the ethics committee of the Institutional Animal Care of Tianjin Medical University Cancer Institute and Hospital.
Highlights
Most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria caused by anti-angiogenic drugs (AADs) according to diabetic nephropathy guidelines or expert recommendations
For the treatment of proteinuria caused by AADs, ACEIs have no efficacy but promote drug resistance
We demonstrate using two different tumor-bearing mouse models that ACEIs do not interfere with the effect of AADs on the VEGF signaling pathway or with the anti-angiogenic effects of the kidney, which indicates that ACEIs have no efficacy for delaying or reducing proteinuria caused by AADs
Summary
Most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria caused by anti-angiogenic drugs (AADs) according to diabetic nephropathy guidelines or expert recommendations. HCC is a typical blood vesselrich tumor, and anti-angiogenesis-related therapies have become the standard treatment for patients with advanced HCC[1,2,3]. The US Food and Drug Administration has approved 4 oral tyrosine kinase inhibitors (TKIs) and 1 anti-angiogenic antibody for the treatment of advanced HCC[4]. AADs improve the overall survival of patients with HCC, but their side effects may require the administered dose to be reduced, thereby limiting the clinical benefit[7]. Except for proteinuria, hand-foot syndrome and hypertension can be well controlled, and good management strategies for these side effects have been developed according to previous clinical experience. Good management of AAD-related proteinuria plays a vital role in ensuring the efficacy of anti-angiogenic therapy and the stable development of new therapies targeting this pathway[8]. The side effects of AAD-related proteinuria have been well described in numerous experimental and clinical studies, to date, no strategy has been established to reduce proteinuria[12,13,14]
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