Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma
Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma
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DOI：
10.1007/s13277-016-4785-8
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发表时间：
2016-01
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影响因子：
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通讯作者：
K. Vaeteewoottacharn;R. Kariya;Paweena Dana;Sawako Fujikawa;K. Matsuda;K. Ohkuma;Eriko Kudo;Ratthaphol Kraiklang;C. Wongkham;S. Wongkham;S. Okada
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文献类型：
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作者：
K. Vaeteewoottacharn;R. Kariya;Paweena Dana;Sawako Fujikawa;K. Matsuda;K. Ohkuma;Eriko Kudo;Ratthaphol Kraiklang;C. Wongkham;S. Wongkham;S. Okada
胆管癌（CCA）是一种独特的肝癌亚型，其发病率在全球范围内呈上升趋势。缺乏特异性症状和明确的诊断标志物导致诊断延迟和疾病进展。全身化疗是治疗晚期CCA的常用方法，尽管其优势尚不清楚。靶向治疗，特别是抗血管内皮生长因子（VEGF）治疗，是有希望的CCA;然而，在治疗方案的改进是必要的，以克服随后的阻力。我们证明VEGF在CCA细胞系中的表达高于其他肝癌细胞。分泌的VEGF在诱导肿瘤内和肿瘤内血管形成中发挥作用。贝伐珠单抗的VEGF中和作用主要通过抑制血管生成有效降低了肿瘤生长;然而，低氧诱导因子1α（HIF 1 α）和HIF 1 α应答基因（如VEGF、VEGFR 1、VEGFR 2、碳酸酐酶（CA）IX和CAXII）的表达增加表明了后续治疗耐药的可能性。补充碳酸酐酶抑制剂乙酰唑胺可增强贝伐单抗的抗CCA作用。联合用药可明显抑制血管生成和细胞增殖。这些结果提示了一种新的治疗策略，以克服抗血管生成耐药性和“诱导必要性”在治疗CCA的重要性。
Cholangiocarcinoma (CCA) is a unique liver cancer subtype with an increasing incidence globally. The lack of specific symptoms and definite diagnostic markers results in a delayed diagnosis and disease progression. Systemic chemotherapy is commonly selected for advanced CCA even though its advantages remain unknown. Targeted therapy, especially anti-vascular endothelial growth factor (VEGF) therapy, is promising for CCA; however, improvements in the therapeutic regimen are necessary to overcome subsequent resistance. We demonstrated VEGF expression was higher in CCA cell lines than in other liver cancer cells. Secreted VEGFs played roles in the induction of peri- and intra-tumoral vascularization. VEGF neutralization by bevacizumab effectively reduced tumor growth, mainly through the suppression of angiogenesis; however, increases in the expression of hypoxia-inducible factor 1α (HIF1α) and HIF1α-responsive genes (such as VEGF, VEGFR1, VEGFR2, carbonic anhydrase (CA) IX and CAXII) indicated the potential for subsequent therapeutic resistance. Supplementation with a carbonic anhydrase inhibitor, acetazolamide, enhanced the anti-CCA effects of bevacizumab. Anti-angiogenesis and anti-proliferation were observed with the combination treatment. These results suggested a novel treatment strategy to overcome anti-angiogenesis resistance and the importance of “induced essentiality” in the treatment of CCA.