Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target.
ABSTRACT Isoform IX of the zinc enzyme carbonic anhydrase (CA, EC 188.8.131.52), CA IX, is a transmembrane protein involved in solid tumor acidification through the HIF-1alpha activation cascade. CA IX has a very high catalytic activity for the hydration of carbon dioxide to bicarbonate and protons, even at acidic pH values (of around 6.5), typical of solid, hypoxic tumors, which are largely unresponsive to classical chemo- and radiotherapy. Thus, CA IX is used as a marker of tumor hypoxia and as a prognostic factor for many human cancers. CA IX is involved in tumorigenesis through many pathways, such as pH regulation and cell adhesion control. The X-ray structure of the catalytic domain of CA IX has been recently reported, being shown that CA IX has a typical alpha-CA fold. However, the CA IX structure differs significantly from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulfide bond. The active site clefts and the proteoglycan (PG) domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. As all mammalian CAs, CA IX is inhibited by several main classes of inhibitors, such as the inorganic anions, the sulfonamides and their bioisosteres (sulfamates, sulfamides, etc.), the phenols, and the coumarins. The mechanism of inhibition with all these classes of compounds is understood at the molecular level, but the sulfonamides and their congeners have important applications. It has been recently shown that both in vitro, in cell cultures, as well as in animals with transplanted tumors, CA IX inhibition with sulfonamides lead to a return of the extracellular pH to more normal values, which leads to a delay in tumor growth. As a consequence, CA IX represents a promising antitumor target for the development of anticancer agents with an alternative mechanism of action.
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ABSTRACT: Much effort is currently devoted to developing patient-specific cancer therapy based on molecular characterization of tumors. In particular, this approach seeks to identify driver mutations that can be blocked through small molecular inhibitors. However, this approach is limited by extensive intratumoral genetic heterogeneity, and, not surprisingly, even dramatic initial responses are typically of limited duration as resistant tumor clones rapidly emerge and proliferate. We propose an alternative approach based on observations that while tumor evolution produces genetic divergence, it is also associated with striking phenotypic convergence that loosely correspond to the well-known cancer "hallmarks". These convergent properties can be described as driver phenotypes and may be more consistently and robustly expressed than genetic targets. To this purpose, it is necessary to identify strategies that are critical for cancer progression and metastases, and it is likely that these driver phenotypes will be closely related to cancer "hallmarks". It appears that an antiacidic approach, by targetting a driver phenotype in tumors, may be thought as a future strategy against tumors in either preventing the occurrence of cancer or treating tumor patients with multiple aims, including the improvement of efficacy of existing therapies, possibly reducing their systemic side effects, and controlling tumor growth, progression, and metastasis. This may be achieved with existing molecules such as proton pump inhibitors (PPIs) and buffers such as sodium bicarbonate, citrate, or TRIS.Cancer and metastasis reviews 11/2014; 33(4). DOI:10.1007/s10555-014-9531-3 · 6.45 Impact Factor
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ABSTRACT: Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues and its selective inhibition provides potential target for treatment against numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anti-cancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring were designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzene sulfonamide group. The bulky ortho substituents such as cyclooctyl or even cyclododecyl groups fit to the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound cocrystal structure with the chimeric CA IX. The strongest inhibitor of recombinant human CA IX catalytic domain produced in human cells achieved the affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound which showed the best balance between affinity and selectivity properties bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.Journal of Medicinal Chemistry 10/2014; 57(22). DOI:10.1021/jm501003k · 5.48 Impact Factor
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ABSTRACT: Drug delivery nanocarriers, especially targeted drug delivery by liposomes are emerging as a class of therapeutics for cancer. Early research results suggest that liposomal therapeutics enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumors and active cellular uptake. Here, we highlight the features of immunoliposomes that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While a large number of studies has been published, the emphasis here is placed on the carbonic anhydrase IX (CA-IX) and the conjugated liposomes that are likely to open a new chapter on drug delivery system by using immunoliposomes to deliver anticancer ingredients to cancer cells in vivo.International Journal of Molecular Sciences 12/2014; 16(1):230-255. DOI:10.3390/ijms16010230 · 2.34 Impact Factor