Abstract
At present, anti-angiogenic drugs (AADs) are widely used in the systemic treatment of hepatocellular carcinoma (HCC) or other types of cancer, and have achieved good anti-cancer effect, whereas treatment-related proteinuria can affect the routine use of AADs, which in turn abates the overall efficacy. Currently, most clinicians prescribe angiotensin-converting enzyme inhibitors (ACEIs) to alleviate proteinuria according to diabetic nephropathy guidelines or expert recommendations. However, the efficacy of ACEIs in reducing AAD-related proteinuria and its effect on the anticancer effect of AADs is unknown. Our clinical data showed that some HCC patients experienced tumor progression by ACEIs administration for the treatment of proteinuria caused by AADs. Here, we 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 the 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. In conclusion, for the treatment of proteinuria caused by AADs, ACEIs have no efficacy while also promoting AADs resistance. This finding is of great significance to guide clinical standardized management of side effects of anti-angiogenic therapy for cancer patients.
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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