Heparan Sulfate Proteoglycan-Mediated Entry Pathway for Charged Tri-Platinum Compounds: Differential Cellular Accumulation Mechanisms for Platinum

Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia 23284, United States.
Molecular Pharmaceutics (Impact Factor: 4.38). 04/2012; 9(6):1795-802. DOI: 10.1021/mp300098t
Source: PubMed


We examined the mechanism of accumulation of charged polynuclear platinum complexes (PPCs) based on analogy of polyarginine interactions with the cell surface heparan sulfate proteoglycan (HSPG) family of protein-linked glycosoaminoglycan polysaccharides (GAGs). GAGS such as heparan sulfate (HS) and chondroitin sulfate (CS) mediate the cellular entry of many charged molecules. Fluorescence microscopy and flow cytometry showed that PPCs, but not the neutral cisplatin or oxaliplatin, blocked the cellular entry of TAMRA-R(9) (a nonarginine peptide, R(9)) coupled to the TAMRA fluorescent label 5-(and 6-)carboxytetramethylrhodamine) in Chinese hamster ovary (CHO), human colon carcinoma (HCT116), and osteosarcoma (SAOS-2) cells. Furthermore, detection of platinum accumulation in wt CHO, mutant CHO-pgsD-677 (lacking HS), and CHO-pgsA (lacking HS/CS) cells confirms that HSPG-mediated interactions are an important mechanism for PPC internalization but not so for uncharged cisplatin and oxaliplatin. Endocytosis inhibitor studies show that macropinocytosis, a mechanism of cell entry for heparan sulfate GAGs and arginine-rich peptides, is important in the cellular accumulation of noncovalent TriplatinNC and, to a lesser degree, the covalently binding BBR3464. Clathrin-mediated endocytosis, however, was not involved in either case. Overall, the results suggest a new proteoglycan-mediated mechanism for cellular accumulation of PPCs not shared by cisplatin or oxaliplatin. The results have significant implications for the rational design of platinum antitumor drugs with distinct biological profiles in comparison to those of the clinically used agents as well as expanding the chemotypes for HS proteoglycan-dependent receptors.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Since the introduction of cisplatin to oncology in 1978, Pt(II) and Pd(II) compounds have been intensively studied with a view to develop the improved anticancer agents. Polynuclear polyamine complexes, in particular, have attracted special attention, since they were found to yield DNA adducts not available to conventional drugs (through long-distance intra- and interstrand cross-links) and to often circumvent acquired cisplatin resistance. Moreover, the cytotoxic potency of these polyamine-bridged chelates is strictly regulated by their structural characteristics, which renders this series of compounds worth investigating and their synthesis being carefully tailored in order to develop third-generation drugs coupling an increased spectrum of activity to a lower toxicity. The present paper addresses the latest developments in the design of novel antitumor agents based on platinum and palladium, particularly polynuclear chelates with variable length aliphatic polyamines as bridging ligands, highlighting the close relationship between their structural preferences and cytotoxic ability. In particular, studies by vibrational spectroscopy techniques are emphasised, allowing to elucidate the structure-activity relationships (SARs) ruling anticancer activity.
    No preview · Article · Feb 2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: a] Maurizio Losacco, [b] and Giovanni Natile [a] Keywords: Bioinorganic chemistry / Medicinal chemistry / Drug design / Drug delivery / Antitumor agents / Platinum / Copper transport proteins Cisplatin, or cis-diamminedichloridoplatinum(II) cis-[PtCl 2 -(NH 3) 2 ], is a platinum-based anticancer drug largely used for the treatment of various types of cancers, including ovarian and colorectal carcinomas, sarcomas, and lymphomas. To-gether with other platinum-based drugs, it triggers malig-nant cell death by binding to nuclear DNA, which appears to be the ultimate target. In addition to passive diffusion ac-ross the cell membrane, other transport mechanisms,
    Full-text · Article · May 2013 · European Journal of Inorganic Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: Simultaneous multi-element imaging using NanoSIMS (nano-scale secondary ion mass spectrometry), exploiting the novel combination of (195)Pt and (15)N in platinum-am(m)ine antitumour drugs, provides information on the internalisation and subcellular localisation of both metal and ligands, and allows identification of ligand exchange.
    No preview · Article · May 2013 · Chemical Communications
Show more