Drugs containing platinum are among the most powerful and widely used cancer drugs. However, such drugs have toxic side effects, and cancer cells can eventually become resistant to them. The Food and Drug Administration (FDA)-approved platinumbased antitumor drugs, cisplatin [cis-diamminedichloroplatinum ( II)], carboplatin [cis-diammine(1,1′-cyclobutanedicarboxylato)- platinum(II)], and oxaliplatin [(R,R)-1,2-diaminocyclohexane) oxalatoplatinum(II)], are currently among the most effective chemotherapies in clinical use for the treatment of cancers. These Pt-based anticancer agents typically form bifunctional intra- and interstrand DNA cross-links through covalent bond with purine nucleobases. These cross-links inhibit transcription and result in cell death. Platinum-based drugs are limited by side effects and poor activity in certain types of cancer resulting from acquired or intrinsic resistance. These limitations evoke a need for new platinum-based chemotherapeutics with novel mechanisms of action.
MIT chemistry professor Stephen J. Lippard, who has spent much of his career studying platinum drugs, has now identified a compound that kills cancer cells better than cisplatin, the most commonly used platinum anticancer drug. The new compound may be able to evade cancer-cell resistance to conventional platinum compounds. “I’ve long believed that there’s something special about platinum and its ability to treat cancer,” Lippard says. Using new variants, “we might have a chance of applying platinum to a broader range of cancer types, more successfully,” he says. Lippard is senior author of a paper describing the new drug candidate, known as phenanthriplatin, in the Proceedings of the National Academy of Sciences (PNAS). Lead author is postdoc Ga Young Park; other authors are graduate student Justin Wilson and postdoc Ying Song.
The unique features of pyriplatin strongly encouraged further study of monofunctional Pt(II) compounds as anticancer drug candidates. Because pyriplatin is more than 10-fold less potent than cisplatin or oxaliplatin, it was of interest to explore analogs with improved activity. We therefore devised a strategy, based on our understanding of the structure of pyriplatin on DNA in pol II, to synthesize other monofunctional platinum compounds that might act more efficaciously as anticancer drugs and to investigate how cells process the specific lesions induced by these previously untried candidates. To improve the potency and cellular uptake of monofunctional Pt(II) complexes, various N-heterocyclic ligands (Am) were substituted for pyridine and the resulting compounds were fully characterized and evaluated for biological activity. Among them, phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl]NO3, was identified to exhibit greater efficacy than cisplatin and oxaliplatin in established human cancer cell lines. The cellular uptake, DNA binding, and transcription-inhibition properties of phenanthriplatin were investigated to provide insight into the high potency of this compound.
Phenanthriplatin was tested against 60 types of cancer cells as part of the National Cancer Institute’s cancer-drug screening program, and it was found to be four to 40 times more potent than cisplatin, depending on the cancer type. It also showed a different pattern of activity than that of cisplatin, suggesting that it could be used to treat types of cancer against which cisplatin is ineffective. One reason for the efficacy of phenanthriplatin is that it can get into cancer cells more easily than cisplatin, Lippard says. Previous studies have shown that platinum compounds containing carbon can pass through specific channels, found in abundance on cancer cells, that allow positively charged organic compounds to enter. Another reason is the ability of phenanthriplatin to inhibit transcription, the process by which cells convert DNA to RNA in the first step of gene expression. Another advantage of phenanthriplatin is that it seems to be able to evade some of cancer cells’ defences against cisplatin. Sulfur-containing compounds found in cells, such as glutathione, can attack platinum and destroy it before it can reach and bind to DNA. However, phenanthriplatin contains a bulky three-ring attachment that appears to prevent sulfur from inactivating the platinum compounds as effectively.
Among the series of recent monofunctional, cationic platinum(II) compounds, phenanthriplatin destroys cancer cells with greater efficacy than either cisplatin or oxaliplatin. Our data indicate that the higher cytotoxicity of phenanthriplatin originates from its efficient cellular uptake and strong transcription inhibitory properties. Studies of its reactivity toward cellular components reveal efficient binding to nucleobases, typically required of an active platinum drug, but retarded reactivity toward a sulfurcontaining nucleophile, such as those associated with cellular resistance mechanisms. An important feature of phenanthriplatin is that its spectrum of activity against panels of cells does not match those of the FDA-approved platinum-based drugs. Phenanthriplatin may therefore be effective against cancer types that are typically resistant to platinum therapy.
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