Ganguly Avishek, Chakraborty Paramita, Banerjee Kaushik, Choudhuri Soumitra Kumar
Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India.
Eur J Pharm Sci. 2014 Jan 23;51:96-109. doi: 10.1016/j.ejps.2013.09.003. Epub 2013 Sep 14.
Drug resistance is a problem that hinders the numerous successes of chemotherapeutic intervention of cancer and continues to be a major obstacle for cures. Till date, several attempts have been made to develop suitable multidrug resistance (MDR) reversing agents. But, throughout the clinical development of MDR reversing agents, patients repeatedly suffer from toxicities. So far, some anticancer activity of Schiff bases which are the condensation products of carbonyl compounds and primary amines and their metal complexes has been described. But, overcoming multidrug resistance, by the use of such small molecules still remain unexplored. Under this backdrop, in search of less toxic and more effective MDR reversing agents our laboratory has developed the different metal chelates of Schiff base N-(2-hydroxy acetophenone)glycinate (NG) which is structurally similar to azatyrosine [L-β-(5-hydroxy-2-pyridyl)-alanine] that inhibits tumor formation by deactivating the c-Raf-1 kinase and c-Ha-ras signalling pathway. A decade-long research proposes possible strategies to overcome MDR by exploiting the chemical nature of such metal chelates. In this review we have catalogued the success of metal chelates of NG to overcome MDR in cancer. The review depict that the problem of MDR can be circumvent by synchronized activation of immunogenic cell death pathways that utilize the components of a host's immune system to kill cancer cells in combination with other conventional strategies. The current wealth of preclinical information promises better understanding of the cellular processes underlying MDR reversing activity of metal derivatives of NG and thus exposes several cellular targets for rational designing of new generation of Schiff base metal chelates as MDR reversing agents.
耐药性是一个阻碍癌症化疗干预取得众多成功的问题，并且仍然是治愈癌症的主要障碍。迄今为止，人们已经多次尝试开发合适的多药耐药（MDR）逆转剂。但是，在MDR逆转剂的整个临床开发过程中，患者反复遭受毒性反应。到目前为止，已经描述了一些席夫碱（羰基化合物与伯胺的缩合产物）及其金属配合物的抗癌活性。但是，利用此类小分子克服多药耐药性仍未得到探索。在此背景下，为了寻找毒性更低、更有效的MDR逆转剂，我们实验室开发了席夫碱N-（2-羟基苯乙酮）甘氨酸酯（NG）的不同金属螯合物，其结构与氮杂酪氨酸[L-β-（5-羟基-2-吡啶基）-丙氨酸]相似，后者通过使c-Raf-1激酶和c-Ha-ras信号通路失活来抑制肿瘤形成。长达十年的研究提出了利用此类金属螯合物的化学性质来克服MDR的可能策略。在这篇综述中，我们梳理了NG金属螯合物在克服癌症多药耐药性方面的成功之处。该综述表明，多药耐药性问题可以通过同步激活免疫原性细胞死亡途径来规避，该途径利用宿主免疫系统的成分与其他传统策略相结合来杀死癌细胞。目前丰富的临床前信息有望更好地理解NG金属衍生物多药耐药逆转活性背后的细胞过程，从而揭示几个细胞靶点，以便合理设计新一代席夫碱金属螯合物作为多药耐药逆转剂。
