Angiotensin-converting Enzyme Inhibitors Have Adverse Effects In Anti-angiogenesis Therapy For Hepatocellular Carcinoma

Background and ObjectiveAt present,anti-angiogenic drugs(AADs)have been widely used in the systemic treatment of hepatocellμlar carcinoma(HCC)or other types of cancer,and have achieved good anti-cancer effects.Whether it is used alone or in combination with other drugs,anti-angiogenesis therapy will be the main choice for systemic treatment of HCC in the future.These drugs improve the overall survival rate of patients with HCC,but their side effects may affect the dose intensity of the drugs and thus affect the clinical benefit.Except for proteinuria,most of the side effects,including hand-foot syndrome and hypertension,can be better controlled clinically.Although the side effects of AADs-related proteinuria are well described in many experiments and clinical data,there is still no good management strategy for eliminating or reducing proteinuria caused by AADs.In the process of tumor anti-angiogenesis therapy,renal toxicity related to the pharmacological inhibition of renal vascular endothelial growth factor(VEGF)signaling and its downstream pathways is still an open question.Therefore,proteinuria caused by anti-angiogenesis therapy becomes the main side effect affecting the normal and continuous use of AADs,thereby reducing the overall efficacy of AADs.At present,most clinicians will give angiotensin converting enzyme inhibitors(ACEIs)or angiotensin II receptor blockers(ARB)drugs based on diabetic nephropathy guidelines,expert recommendations or drug instructions,in order to reduce protein occurrence or lessen the degree of proteinuria.However,whether ACEIs can alleviate AADs-related proteinuria and its influence on the anticancer effect of AADs is unclear.In our clinical work,we found that the application of ACEIs did not effectively relieve proteinuria.On the contrary,some cases of using ACEIs showed that the anti-cancer ability of AADs was significantly reduced.Through investigating the literature,we found that whether ACEIs promote cancer is controversial.In particμlar,a case report presented that multiple ACEIs reduced the efficacy of bevacizumab in the treatment of ovarian cancer,which is consistent with our clinical phenomenon.Methods and resultsWe used two tumor-bearing mouse models of immunogenicity and immunodeficiency,three representative ACEIs drugs,and two anti-angiogenic drugs with a high incidence of proteinuria to repeatedly observe the effects of ACEIs on AADs-related proteinuria and its anti-cancer efficacy.We first determined the optimal dose of ACEIs and AADs.In observing the effect on proteinuria,the experimental results show that ACEIs cannot delay or reduce proteinuria and kidney damage caused by AADs,and at the same time do not affect the disappearance of proteinuria and the recovery of glomerular damage after AADs are stopped;In terms of anti-cancer efficacy,ACEIs not only reduced the anti-cancer efficacy of anti-angiogenic drugs,but also promoted liver and lung metastasis in liver cancer subcutaneous tumor models with high metastatic potential.In terms of mechanism research,we found that the combination of ACEIs and AADs reduced the anti-angiogenesis effect of AADs.This effect is not caused by changes in the VEGF signaling pathway,but due to the excessive production of renal-derived erythropoietin(EPO)caused by the combined use of ACEIs and AADs.We blocked the EPO signaling pathway and reversed this phenomenon.ConclusionIn short,ACEIs cannot delay and alleviate proteinuria and kidney damage caused by anti-angiogenic drugs,but instead enhance the increase in renal EPO production caused by systemic anti-angiogenic drugs,which in turn leads to desensitization of tumors to AADs.That is,ACEIs can not only reduce or delay proteinuria caused by anti-angiogenic drugs,but also reduce the anti-cancer efficacy of anti-angiogenic drugs.This discovery is of great significance for guiding the standardized management of side effects of anti-angiogenesis therapy in cancer patients.It is worth looking forward to explore the pathogenesis of AADs-related proteinuria,so as to find a solution that can reduce proteinuria without reducing the anti-cancer efficacy of AADs.