Dicycloplatin was developed in China and it was used for phase I human trial clinical in 2006. The drug was approved for chemotherapy by the Chinese FDA in 2012.[3]
Dicycloplatin consists of carboplatin and cyclobutane-1,1-dicarboxylic acid (CBDC) linked by the hydrogen bond. In the structure of dicycloplatin, there are two types of bond: O-H...O is the bond between the hydroxyl group of CBDC with carboxyl oxygen atom. It creates the one-dimensional polymer chain of carboplatin and CBDC. The second one is N-H...O which links between the ammonia group of carboplatin and oxygen of CBDC. It forms the two-dimensional polymer chain of carboplatin and CBDC. In aqueous solution, the 2D-hydrogen bonded polymeric structure of dicycloplatin is destroyed. Firstly, the bond between ammonia group of carboplatin and oxygen of CBDC breaks, thus inducing the formation of one-dimensional dicycloplatin. After that, the strong hydrogen bond breaks and creates an intermediate state of dicycloplatin. Finally, the rearrangement of different orientation of carboplatin and CBDC leads to the formation of intramolecular hydrogen bond and a supramolecule of dicycloplatin with two O-H...O and N-H...O is created.[5]
Similar to carboplatin, dicycloplatin inhibits the proliferation of cancer cells by inducing cell apoptosis. When treated with dicycloplatin, some changes in the properties of Hep G2 cells are observed: the declination of Mitochondria Membrane Potential, the release of cytochrome c from mitochondria to cytosol, the activation of caspase-9, caspase-3 and the decrease of Bcl-2.[2] Those phenomena indicate the role of mitochondrial in the apoptosis by intrinsic way.[6] Furthermore, the increase in caspase-8 activation is also observed. This can stimulate the apoptosis by activating downstream caspase-3[7] or by cleaving Bid.[8] As a result, the cleavage of Bid (tBid) transfers to the mitochondria and induce mitochondrial dysfunction which promotes the release of cytochrome c from mitochondria to cytosol.[9] From the dicycloplatin-treated Hep G2 cell, an excessive amount of reactive oxygen species was detected,[2] which plays an important role in the release of cytochrome c. In the mitochondria, the release of hemoprotein happens through 2-step process: Firstly, the dissociation of cytochrome c from its binding to cardiolipin happens. Due to the reactive oxygen species, the cardiolipin is oxidized, thus reducing the cytochrome c binding and increase the concentration of free cytochrome c.[10]
^Zhao D, Zhang Y, Xu C, Dong C, Lin H, Zhang L, et al. (August 2012). "Pharmacokinetics, tissue distribution, and plasma protein binding study of platinum originating from dicycloplatin, a novel antitumor supramolecule, in rats and dogs by ICP-MS". Biological Trace Element Research. 148 (2): 203–8. doi:10.1007/s12011-012-9364-2. PMID22367705. S2CID16035022.
^Li S, Huang H, Liao H, Zhan J, Guo Y, Zou BY, et al. (February 2013). "Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results". International Journal of Clinical Pharmacology and Therapeutics. 51 (2): 96–105. doi:10.5414/CP201761. PMID23127487.
^Yang X, Jin X, Song Q, Tang K, Yang Z, Zhang X, Tang Y (June 2010). "Structural studies of dicycloplatin, an antitumor supramolecule". Science China Chemistry. 53 (6): 1346–1351. doi:10.1007/s11426-010-3184-z. S2CID97893314.
^Yang BF, Xiao C, Li H, Yang SJ (December 2007). "Resistance to Fas-mediated apoptosis in malignant tumours is rescued by KN-93 and cisplatin via downregulation of c-FLIP expression and phosphorylation". Clinical and Experimental Pharmacology & Physiology. 34 (12): 1245–51. doi:10.1111/j.1440-1681.2007.04711.x. PMID17973862. S2CID40501734.
^Yin XM (March 2006). "Bid, a BH3-only multi-functional molecule, is at the cross road of life and death". Gene. 369: 7–19. doi:10.1016/j.gene.2005.10.038. PMID16446060.
