Department of Radiation, Oncology, University of Wurzburg, Josef-Schneider Strasse 11, Wurzburg, Germany.
Curr Pharm Des. 2010;16(29):3288-99. doi: 10.2174/138161210793429788.
Hypoxia is a crucial factor in tumour aggressiveness and its treatment resistance, particularly in human brain cancer. Tumour resistance against radiation- and chemo- therapy is facilitated by oxygenation reduction at tumour areas. HIF-1α regulated genes are mostly responsible for this type of resistance. Among these genes, carbonic anhydrase isoform 9 (CA9) is highly overexpressed in many types of cancer especially in high grade brain cancer like GBM. CA IX contributes to tumour environment acidification by catalyzing the carbon dioxide hydration to bicarbonate and protons, leading to the acquisition of metastasic phenotypes and chemoresistance to weakly basic anticancer drugs and therefore to inadequate application of radio-therapeutic or chemotherapeutic anti-cancer treatment strategies. Inhibition of this enzymatic activity by application of specific chemical CA9 inhibitors (sulphonamide derivative compounds) or indirect inhibitors like HIF-1α inhibitors (chetomin) or molecular inhibitors like CA9-siRNA leads to reversion of these processes, leading to the CA9 functional role inhibition during tumourigenesis. Hypoxia significantly influences the tumour microenvironment behaviour via activation of genes involved in the adaptation to the hypoxic stress. It also represents an important cancer prognosis indicator and is associated with aggressive growth, malignant progression, metastasis and poor treatment response. The main objective in malignant GBM therapy is either to eradicate the tumour or to convert it into a controlled, quiescent chronic disease. Sulfonamide derivative compounds with CA9 inhibitory characteristics represent one of the optimal treatment options beside other CA9 inhibitory agents or chemical inhibitory compounds against its main regulating transcription factor which is the hypoxia induced HIF-1α when applied against human cancers with hypoxic regions like GBM, bearing potential for an effective role in human brain tumour therapeutic strategies. Glycolytic inhibitors, when added in controlled doses under hypoxia, lead to a reduced accumulation of HIF-1α and can function as indirect hypoxia regulated genes inhibitors like CA9. These may be used as alternative or in conjunction with other direct inhibitors like the sulphonamide derivate compounds, chetomin or specific siRNAs, or other different chemical compounds possessing similar functionality making them as optimal tools for optimized therapy development in cancer treatment, especially against human brain cancer. Further experimental analysis towards the tumour stage specific inhibitory CA9 characteristics determination are necessary to find the optimal therapeutic solutions among the different available modalities; whether they are direct or indirect chemical, molecular or natural inhibitors to be able to set up successful treatment approaches against the different human tumour diseases.
缺氧是肿瘤侵袭性和治疗耐药性的关键因素，特别是在人脑癌中。肿瘤对放疗和化疗的耐药性是通过肿瘤区域的氧合还原来促进的。HIF-1α 调节的基因主要负责这种类型的耐药性。在这些基因中，碳酸酐酶同工酶 9（CA9）在许多类型的癌症中高度过表达，特别是在高级别脑癌如 GBM 中。CA9 通过催化二氧化碳水合作用生成碳酸氢盐和质子，促进肿瘤环境酸化，从而获得转移表型和对弱碱性抗癌药物的化疗耐药性，因此无法充分应用放射治疗或化学抗癌治疗策略。通过应用特定的化学 CA9 抑制剂（磺胺衍生物化合物）或间接抑制剂（如 HIF-1α 抑制剂）或分子抑制剂（如 CA9-siRNA）来抑制这种酶活性，可导致这些过程的逆转，从而在肿瘤发生过程中抑制 CA9 的功能作用。缺氧通过激活适应低氧应激的基因显著影响肿瘤微环境行为。它也是一个重要的癌症预后指标，与侵袭性生长、恶性进展、转移和治疗反应不良有关。恶性 GBM 治疗的主要目标是要么根除肿瘤，要么将其转化为可控的、静止的慢性疾病。具有 CA9 抑制特性的磺胺衍生物化合物是除其他 CA9 抑制剂或针对其主要调节转录因子缺氧诱导的 HIF-1α 的化学抑制化合物之外的最佳治疗选择之一，当应用于具有缺氧区域的人类癌症（如 GBM）时，具有在人类脑肿瘤治疗策略中发挥有效作用的潜力。在缺氧下以受控剂量添加糖酵解抑制剂会导致 HIF-1α 的积累减少，并可作为间接缺氧调节基因抑制剂（如 CA9）。这些可作为替代物或与其他直接抑制剂（如磺胺衍生物化合物、chetomin 或特定的 siRNA）联合使用，或与具有相似功能的其他不同化学化合物联合使用，使它们成为癌症治疗中优化治疗开发的最佳工具，特别是针对人脑癌。需要进一步进行肿瘤阶段特异性抑制 CA9 特征的实验分析，以在不同的可用模式中找到最佳的治疗解决方案；无论是直接的还是间接的化学的、分子的还是天然的抑制剂，以建立针对不同人类肿瘤疾病的成功治疗方法。
