(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells. This prompted us to perform detailed studies to confirm or rule out the role of RRD2 binding to DNA in its antiproliferative effect in cancer cells. Here, we show that RRD2 exhibits excellent antiproliferative activity in various cancer cell lines, with IC50 values in the low micromolar or submicromolar range. Moreover, the results of this study demonstrate that DNA lesions caused by RRD2 contribute to killing cancer cells treated with this phosphaplatin derivative. Additionally, our data indicate that RRD2 accumulates in cancer cells but to a lesser extent than cisplatin. On the other hand, the efficiency of cisplatin and RRD2, after they accumulate in cancer cells, in binding to nuclear DNA is similar. Our results also show that RRD2 in the medium, in which the cells were cultured before RRD2 accumulated inside the cells, remained intact. This result is consistent with the view that RRD2 is activated by releasing free pyrophosphate only in the environment of cancer cells, thereby allowing RRD2 to bind to nuclear DNA.

• Klíčová slova
• Anticancer, Cisplatin, DNA, Mechanism of action, Oxaliplatin, Phosphaplatin,
• MeSH
• cisplatina farmakologie   MeSH
• difosfáty farmakologie   MeSH
• DNA metabolismus   MeSH
• nádory * MeSH
• organoplatinové sloučeniny farmakologie   metabolismus   MeSH
• oxaliplatin farmakologie   MeSH
• platina farmakologie   MeSH
• protinádorové látky * farmakologie   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• difosfáty MeSH
• diphosphoric acid MeSH Prohlížeč
• DNA MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH
• platina MeSH
• protinádorové látky * MeSH

The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl2], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl2] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis-1,3-DACH)Cl2] originates from its highest hydrophobicity and most efficient cellular uptake.

• Klíčová slova
• Antitumor, Cellular uptake, DNA, Glutathione, Oxaliplatin, Pt(1,n-diaminocycloalkane) moiety,
• MeSH
• apoptóza účinky léků   MeSH
• cisplatina farmakologie   normy   MeSH
• cyklické uhlovodíky chemická syntéza   MeSH
• DNA chemie   MeSH
• glutathion chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• organokovové sloučeniny chemická syntéza   farmakologie   MeSH
• permeabilita buněčné membrány MeSH
• platina chemie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• cyklické uhlovodíky MeSH
• DNA MeSH
• glutathion MeSH
• organokovové sloučeniny MeSH
• platina MeSH
• protinádorové látky MeSH