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![Mobility of the ligation products of duplexes [1,4; 5– 5(20 –23)] containing a single, site-specific interstrand CL of BBR3464 on 8% polyacrylamide gel. A, autoradiogram of the ligation products. The duplexes contained a unique 1,4-interstrand CL formed by BBR3464 between the central G residue in the top strand and the G residue in the bottom strand oriented in the 5 3 5 direction (see " Results " ). Pt lanes, interstrand cross-linked duplexes; NoPt lane, unplatinated duplexes. B, plots showing the relative mobility K versus sequence length curves for oligomers 20 –23 bp long denoted as 20-mer, 21-mer, 22-mer, and 23-mer, respectively. C, plot showing the relative mobility K versus interadduct distance in bp for oligomers 20 –23 bp long with a total length of 132 bp. The experimental points represent the average of three independent electrophoresis experiments. The curve represents the best fit of these experimental points to the equation K ad 2 bd c (49).](profile/Viktor-Brabec/publication/11163737/figure/fig5/AS:449339697963008@1484142340029/Mobility-of-the-ligation-products-of-duplexes-1-4-5-520-23-containing-a-single.png)
Mobility of the ligation products of duplexes [1,4; 5– 5(20 –23)] containing a single, site-specific interstrand CL of BBR3464 on 8% polyacrylamide gel. A, autoradiogram of the ligation products. The duplexes contained a unique 1,4-interstrand CL formed by BBR3464 between the central G residue in the top strand and the G residue in the bottom strand oriented in the 5 3 5 direction (see " Results " ). Pt lanes, interstrand cross-linked duplexes; NoPt lane, unplatinated duplexes. B, plots showing the relative mobility K versus sequence length curves for oligomers 20 –23 bp long denoted as 20-mer, 21-mer, 22-mer, and 23-mer, respectively. C, plot showing the relative mobility K versus interadduct distance in bp for oligomers 20 –23 bp long with a total length of 132 bp. The experimental points represent the average of three independent electrophoresis experiments. The curve represents the best fit of these experimental points to the equation K ad 2 bd c (49).
Source publication
The novel phase II antitumor polynuclear platinum drug BBR3464 ([(trans-PtCl(NH(3))(2))(2)(mu-trans-Pt(NH(3))(2)(NH(2)(CH(2))(6)NH(2))(2))](NO(3))(4)) forms intra- and interstrand cross-links (CLs) on DNA (which is the pharmacological target of platinum drugs). We examined first in our recent work how various intrastrand CLs of BBR3464 affect the c...
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... experimental details of these studies are given in our recent report describing DNA intrastrand CLs of BBR3464 (12). Autoradiograms of electrophoresis gels revealing resolu- tion of the ligation products of unplatinated 20 -23-bp duplexes [1,4;5-5(20 -23)] or containing a unique 1,4-GG interstrand CL of BBR3464 in the 5 3 5 direction are shown in Fig. 5A. A small but significant retardation was observed for the mul- timers of all platinated duplexes. The K factor is defined as the ratio of calculated to actual length. The variation of the K factor versus sequence length obtained for multimers of the duplexes 20 -23 bp long and containing the unique 1,4-GG interstrand CL of BBR3464 in ...
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... retardation was observed for the mul- timers of all platinated duplexes. The K factor is defined as the ratio of calculated to actual length. The variation of the K factor versus sequence length obtained for multimers of the duplexes 20 -23 bp long and containing the unique 1,4-GG interstrand CL of BBR3464 in the 5 3 5 direction is shown in Fig. 5B. Maximum retardation was observed for the 22-bp cross-linked duplex. This observation suggests that the natural 10.5-bp repeat of B-DNA and that of DNA perturbed by the interstrand CL of BBR3464 are different as a consequence of DNA unwind- ing (49). Similar results were also obtained for the 1,4-GG interstrand CL of BBR3464 formed in ...
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... unwinding angles were calculated from the exact helical repeat of the 1,4-interstrand cross-linked duplexes (49). The maxima of these curves constructed for the interstrand cross- linked duplexes with a total length of 150 bp (shown for the CL in the 5 3 5 direction in Fig. 5C) were determined to be 21.41 0.04 and 21.42 0.04 bp for the CLs in the 3 3 3 and 5 3 5 directions, respectively. Total sequence lengths other than 150 bp were examined and gave identical results. To convert the interadduct distance in base pairs corresponding to the curve maximum into a duplex unwinding angle in degrees, the value was ...
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... evaluation of the relationship between interadduct dis- tance and phasing for self-ligated multimers composed of the identical number of monomeric duplexes (bend units) resulted in a bell-shaped pattern (shown for the CL in the 5 3 5 direction in Fig. 5C) characteristic of bending. Quantitation of the bend angles of the 1,4-interstrand CLs of BBR3464 was performed as described previously (19,33,38,53,54) utilizing the following empirical equation (Equation ...
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... shift assays. Not surprisingly, the HMGB1 protein exhib- ited affinity for the probe containing the 1,2-GG intrastrand CL of cisplatin, as indicated by the presence of a shifted band of the 149-bp probe containing the single 1,2-GG intrastrand CL of cisplatin with the protein (the intensity of which rose with increasing protein concentration) (Fig. 6C, lanes 5-8). The interaction between the protein and the DNA intrastrand cross-linked by cisplatin was not a result of general DNA af- finity for the protein because the protein failed to bind the unmodified 149-bp duplexes under identical conditions (Fig. 6C, lanes 1-4). On the other hand, under the same experimen- tal conditions, the full-length ...
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... with blunt ends were purified as described under "Experimental Procedures" so that their samples contained no contaminating single-stranded DNA, as evident from analysis on native polyacrylamide gel (data not shown). The 21-bp duplex [TGGT] containing a single, site-specific 1,2-GG intrastrand CL of cisplatin was run as a positive control (Fig. 8B, lanes 5-8). The results of the gel mobility shift assay demonstrated that increasing RPA concen- trations resulted in an increasing amount of this protein bound to the 1,2-GG intrastrand CL of cisplatin. On the other hand, the same analysis performed with the undamaged substrate or the substrate containing a single, site-specific 1,4-interstrand ...
Similar publications
The new antitumor trinuclear platinum compound [(trans-PtCl(NH(3))(2))(2)mu-trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2)](4+) (designated as BBR3464) is currently in phase II clinical trials. DNA is generally considered the major pharmacological target of platinum drugs. As such it is of considerable interest to understand the patterns of DNA damage...
Citations
... Therefore, the multivalent platinum agents having two to three platinum units have been developed as alternatives [3]. BBR3464 is a trinuclear platinum compound, where a tetra-amine [trans-Pt(NH 3 ) 2 {H 2 N(CH 2 ) 6 NH 2 } 2 ] 2þ unit links two terminal trans-[PtCl(NH 3 ) 2 ] units ( Fig. 1B) [4]. It is an important anti-cancer agent since it functions at 10e1000 times lower dose limit than cisplatin [3,5] and is effective in cisplatin-resistant cancer cells [3]. ...
... Cisplatin mainly forms intrastrand crosslinks and thereby bends double helix by 50 towards major groove [2]. Bifunctional binding of BBR3464 helps to form intra-strand crosslinks and 1,2-, 1,4-and 1,6-inter-strand crosslinks by its two platinum ends involving guanine residues [4]. In addition to formation of intra-and inter-strand cross-links, both BBR3464 and cisplatin generate loop structures through inter-helix crosslinking [5]. ...
... The inter-strand cross-links pose a special challenge to repair enzymes because they involve both strands of DNA and would not be repaired so readily because the repair enzymes would require the information in the complementary strand for re-synthesis. In this way, the inter-strand crosslinks might persist considerably longer than intra-strand adducts, which would result in enhanced cytotoxicity [4]. The effect of loop structures as a result of inter-helix cross-linking could be even more drastic since the stretch of dsDNA which is contained within the loop remains inaccessible to the replication and transcription machinery since the helicase action is least likely to proceed beyond the knot region inside the loop structure [5]. ...
High mobility group B1 (HMGB1) is an architectural protein that recognizes the DNA damage sites formed by the platinum anticancer drugs. However, the impact of HMGB1 binding on the structural alterations of the platinum drug-treated single dsDNA molecules has remained largely unknown. Herein, the structural alterations induced by the platinum drugs, the mononuclear cisplatin and it's analog the trinuclear BBR3464, have been probed in presence of HMGB1, by atomic force microscopy (AFM) and AFM-based force spectroscopy. It is observed that the drug-induced DNA loop formation enhanced upon HMGB1 binding, most likely as a result of HMGB1-induced increase in DNA conformational flexibility that allowed the drug-binding sites to come close and form double adducts, thereby resulting in enhanced loop formation via inter-helix cross-linking. Since HMGB1 enhances DNA flexibility, the near-reversible structural transitions as observed in the force-extension curves (for 1h drug treatment), generally occurred at lower forces in presence of HMGB1. The DNA structural integrity was largely lost after 24h drug treatment as no reversible transition could be observed. The Young's modulus of the dsDNA molecules, as estimated from the force-extension analysis, increased upon drug treatment, due to formation of the drug-induced covalent cross-links and consequent reduction in DNA flexibility. The Young's modulus increased further in presence of HMGB1 due to HMGB1-induced enhancement in DNA flexibility that could ease formation of the drug-induced covalent cross-links. To our knowledge, this is the first report that shows an increase in the stiffness of the platinum drug-treated DNA molecules in presence of HMGB1.
... Triplatin was originally developed to generate DNA lesions that are distinct from other platinums and less recognizable by DNA repair proteins. The 1,4 DNA interstrand crosslinks produced by Triplatin, unlike the 1,2 intrastrand crosslinks produced by cisplatin/carboplatin, evade binding of high-mobility group proteins and repair by the nucleotide excision repair machinery (42)(43)(44). The results shown here are consistent, in that Triplatin showed similar activity in high sGAGexpressing PDX models, WHIM30 (mtBRCA), and WHIM2 (wtBRCA), regardless of BRCA status, whereas carboplatin was markedly less effective in the WHIM2 model with wtBRCA (37,38). ...
Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive, and when metastatic is often drug resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for TNBC patients. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models to the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor cells, whereas carboplatin followed the opposite trend. In carboplatin-resistant tumor models expressing high levels of sGAGs, Triplatin decreased primary tumor growth, reduced lung metastases, and inhibited metastatic growth in lungs, liver, and ovaries. sGAG levels served as a predictor of Triplatin sensitivity in TNBC. Triplatin may be particularly beneficial in treating patients with chemotherapy-resistant tumors who have evidence of residual disease after standard neoadjuvant chemotherapy. More effective neoadjuvant and adjuvant treatment will likely improve clinical outcome of TNBC.
... BBR3464, a trinuclear platinum (II) complex, forms flexible, "long distance" ICLs over a range up to six DNA base pairs, and these unique DNA lesions are thought to mediate its activity [156,157]. In vitro studies revealed a pattern of BBR3463 cytotoxicity, which was markedly different from that of cisplatin, and it was active in cisplatin resistant colorectal cancer cells [158,159]. ...
Simple Summary
Cisplatin is successfully used for the treatment of various solid cancers. Unfortunately, it shows no activity in colorectal cancer. The resistance phenotype of colorectal cancer cells is mainly caused by alterations in p53-controlled DNA damage signaling and/or defects in the cellular mismatch repair pathway. Improvement of platinum-based chemotherapy in cisplatin-unresponsive cancers, such as colorectal cancer, might be achieved by newly designed cisplatin analogues, which retain activity in unresponsive tumor cells. Moreover, a combination of cisplatin with biochemical modulators of DNA damage signaling might sensitize cisplatin-resistant tumor cells to the drug, thus providing another strategy to improve cancer therapy.
Abstract
Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.
... These adducts include the formation of 1,4-interstrand crosslinks in the 5'!5' and antiparallel 3'!3' direction that are likely to be challenging to remove by nucleotide excision repair and which induce delocalised conformational changes in DNA. [20] In line with these observations, ar ange of dinuclearp latinum complexes,s uch as BBR3610 (Figure 1), have been shown to be significantly more potent than cisplatin in cell culture and animal models. [21] Interestingly,r ecent studies have identified proteoglycansa sa lternative cellular targets for di-andt rinuclearp latinum complexes.T hrough sulfate cluster anchoring, these complexes were found to shield sulfated oligosaccharides from enzymatic degradation,w hereas cisplatin was ineffective. ...
Dinuclear metallodrugs offer much potential in the development of novel anticancer chemotherapeutics as a result of the distinct interactions possible with bio‐macromolecular targets and the unique biological activity that can result. Herein, we describe the development of isostructural homo‐dinuclear OsII–OsII and hetero‐dinuclear OsII–RuII organometallic complexes formed from linking the arene ligands of [M(η⁶‐arene)(C2O4)(PTA)] units (M=Os/Ru; PTA=1,3,5‐triaza‐7‐phosphaadamantane). Using these complexes together with the known RuII–RuII analogue, a chromatin‐modifying agent, we probed the impact of varying the metal ions on the structure, reactivity and biological activity of these complexes. The complexes were structurally characterised by X‐ray diffraction experiments, their stability and reactivity were examined by using ¹H and ³¹P NMR spectroscopy, and their biological activity was assessed, alongside that of mononuclear analogues, through MTT assays and cell‐cycle analysis (HT‐29 cell line). The results revealed high antiproliferative activity in each case, with cell‐cycle profiles of the dinuclear complexes found to be similar to that for untreated cells, and similar but distinct profiles for the mononuclear complexes. These results indicate these complexes impact on cell viability predominantly through a non‐DNA‐damaging mechanism of action. The new OsII–OsII and OsII–RuII complexes reported here are further examples of a family of compounds operating via mechanisms of action atypical of the majority of metallodrugs, and which have potential as tools in chromatin research.
... Polynuclear platinum (II) complexes are capable of forming long-range coordination such as DNA inter-and intra-strand links (Komeda et al., 2010). These links can occur with distances up to 4 pairs of nitrogenous bases (Kasparkova et al., 2002). The charge created by the metal centers increases the binding kinetics with the DNA, because the connection is achieved by two coordination spheres of independent mono-functional platinum, eliminating many problems of steric hindrance which are present when two nucleobases are attached to one Pt atom, such as for cisplatin and its analogs. ...
The class of polynuclear platinum(II) compounds have demonstrated a great interest because their high activity against cancer cells. Among these new compounds, the TriplatinNC also called AH78, demonstrated surprising antitumor activity, in some cases equivalent to cisplatin. It is well-known that complex charge +8 favors interaction with DNA and other biomolecules non-covalently, through the hydrogen bonds with phosphate and sulfate groups present in these structures. The hydrogen atoms of the amine interact with the oxygen atoms of the phosphate and sulfate groups present in the DNA strand and heparan sulfate, respectively. These interactions can cause significant twists in double helix and inhibit the activity of these biomolecules. The present investigation is an attempt to provide a benchmark theoretical study about TriplatinNC. We have described the non-covalent interactions through small reliable mimetic models. The non-covalent interactions were also evaluated on larger models containing DNA fractions with six nitrogenous base pairs (CGCGAA) and fractions of the disaccharide that makes the HS evaluated by the hybrid QM/MM ONIOM methodology.
... Triplatin was originally developed to generate DNA lesions that are distinct from other platinums and less recognizable by DNA repair proteins. Indeed, the 1,4 DNA interstrand crosslinks produced by Triplatin, unlike the 1,2 intrastrand crosslinks produced by cisplatin/carboplatin, evade binding of high mobility group proteins and repair by the nucleotide excision repair machinery (42)(43)(44). The results shown here are consistent, in that Triplatin showed similar activity in high sGAG-expressing PDX models, WHIM30 (mtBRCA) and WHIM2 (wtBRCA), regardless of BRCA status, whereas carboplatin was markedly less effective in the WHIM2 model with wtBRCA (37,38). ...
Heparan sulfate (HS) are linear polysaccharides conjugated to proteins, heparan sulfate proteoglycans (HSPGs), located on the cell surface and extracellular matrix. The HS chains display varying degrees of sulfation. These sulfate clusters mediate the interaction of polynuclear platinum complexes (PPCs) with HSPG through a “sulfate clamp.” Such PPC-HS interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding. The biological consequences of PPCs metalloshielding HS will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation. HSPGs, associated growth factors, and heparanase promote tumor progression by facilitating invasion, angiogenesis, and metastasis. High heparanase expression correlates with increased metastatic potential and poor clinical prognosis. PPC-HS interactions inhibit cleavage of a model pentasaccharide by heparanase and further modulated bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells. The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis. We report proof-of-principle of strong in vivo anti-metastatic activity of PPCs in triple negative breast cancer (TNBC) models. Further, we examine the anti-metastatic and anti-angiogenic effects of PPC-HS metalloshielding in these in vivo models through multiple growth factor signaling pathways (bFGF, HB-EGF, VEGF), and heparanase activity in breast cancer and endothelial cells. PPCs represent a novel class of intrinsically dual-function agents combining platinum cytotoxicity through DNA targeting with anti-angiogenic effects through glycan targeting.
Chicago 14-17 April 2018
Citation Format: Samantha J. Katner, James D. Hampton, Erica J. Peterson, Eriko Katsuta, Megan R. Sayyad, Kazuaki Takabe, Jennifer Koblinski, Nicholas P. Farrell. Heparan sulfate, a new target for platinum in metastatic TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3941.
... This difference in DNA binding offers great potential for overcoming the drug resistance to cisplatin, which is the most prevalent issue that cisplatin faces in the clinic. Farrell et al. have developed a series of MNPt(II)s, of which BBR3571 [37][38][39] and (trans,trans,trans)-bis-mu-(hexane-1,6-diamine)mu-[diammineplatinum(II)]bis[diammine(chloro)platinum(II)] tetranitrate (BBR3464) [40][41][42][43] (Fig. 2B) are the most potent. These compounds demonstrate the ability to overcome cisplatin resistance both in vitro and in vivo [44]. ...
Platinum drugs comprise of almost 50% of all currently used anticancer drugs. They are now widely used in the clinical therapy of various solid tumors, including ovarian, head and neck, colorectal, lung cancers, and so forth. However, their extensive systemic toxicity and the drug resistance acquired by cancer cells limit the applications of platinum drugs. Modern nanobiotechnology provides the possibility for targeted delivery of platinum drugs to the tumor site, thereby minimizing toxicity and optimizing the efficacies of the drugs. Numerous drug delivery carriers, such as polymer nanoparticles, solid lipids, and inorganic nanoparticles, have been developed over the years for delivering platinum drugs. Thus, significant improvements have been made in this field, especially for polymer-based platinum drug delivery systems. In the past five years, particularly interesting studies have been done regarding polymer-based carriers for platinum(IV) drugs, which are chemically inert but can be activated either by intracellular glutathione (GSH) and ascorbic acid (chemically reductive platinum(IV) drugs) or by ultraviolet (UV)/green light (photosensitive platinum(IV) drugs). This review presents a comprehensive overview on the development of various types of polymer-based platinum drug delivery systems. It spans both single-drug carriers and carriers that are combined with other imaging agents, drug sensitizers, and anticancer drugs. Their fabrication methods, mechanisms of action, their applications in cancer therapy, as well as the prospect of their development in the future are also predicted.
... Triplatin was originally developed to generate DNA lesions that are distinct from other platinums and less recognizable by DNA repair proteins. Indeed, the 1,4 DNA interstrand crosslinks produced by Triplatin, unlike the 1,2 intrastrand crosslinks produced by cisplatin/carboplatin, evade binding of high mobility group proteins and repair by the nucleotide excision repair machinery (42)(43)(44). The results shown here are consistent, in that Triplatin showed similar activity in high sGAG-expressing PDX models, WHIM30 (mtBRCA) and WHIM2 (wtBRCA), regardless of BRCA status, whereas carboplatin was markedly less effective in the WHIM2 model with wtBRCA (37,38). ...
The high affinity of polynuclear platinum compounds (PPCs) for heparan sulfate (HS) is mediated through a “sulfate clamp” and PPC interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding.1 Metalloshielding will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation.2 PPCs inhibit cleavage of a model pentasaccharide by heparanase and further modulate bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells.3 The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis.3 Following proof-of-principle of strong in vivo anti-metastatic activity of PPCs in clinically relevant breast cancer models,4 this contribution examines the underlying mechanism of platinums as anti-metastatic agents. We report on the cellular effects of PPC-HS metalloshielding on multiple growth factor signaling pathways (bFGF, HB-EGF) and specific syndecan (Sdc)-dependent signaling in breast cancer. Coupled with previously demonstrated DNA binding, PPCs represent intrinsically dual- function agents combining platinum cytotoxicity with anti-angiogenic effects derived from first principles through glycan targeting.
[1] Mangrum, J.B., Engelmann, B.J., Peterson, E.J., Ryan, J.J., Berners-Price, S.J., Farrell, N.P. Chemical Communications 2014, 50, 4056-4058.
[2] Chiodelli, P., Bugatti, A., Urbinati, C., Rusnati, M. Molecules 2015, 20, 6342-6388.
[3] Peterson, E.J., Daniel, A.G., Katner, S.J., Bohlmann, L., Chang,C., Bezos, A., Parish, C.R., von Itzstein, M., Berners-Price, S.J., Farrell, N.P. Chem. Sci. 2016, DOI: 10.1039/C6SC02515C.
[4] E. Katsuta, S. Demasi, S. Katner, H. Aoki, E. Peterson, E., N.P. Farrell and K. Takabe. (2016). Proc. AACR New Orleans, LA. Abstract #3064.
DC 1-5 April 2017
Citation Format: Samantha J. Katner, Erica Peterson J. Peterson, Eriko Katsuta, Stephanie C. DeMasi, Jennifer Koblinski, Kazuaki Takabe, Nicholas P. Farrell. Anti-metastatic platinum through glycan targeting in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 17. doi:10.1158/1538-7445.AM2017-17
... BBR3464 formed long-range delocalized intra-and inter-strand cross-links between guanines spanning up to six base pairs compared to a maximum of three base pairs in the case of CDDP. DNA adducts induced by BBR3464 lacked severe distortion owing to bending and twisting and were not recognized by high-mobility group (HMG) proteins (Kasparkova et al. 2002). As a result of this DNA binding property, BBR3464 was highly active in various cell lines and overcame resistance in neuroblastoma, ovarian carcinoma, and melanoma cells, each of which had different mechanisms of resistance (Manzotti et al. 2000). ...
A cationic azolato-bridged dinuclear platinum(II) complex, [{cis-Pt(NH3)2}2(μ-OH)(μ-methyl-pyrazolate)](2+) (4M-PzPt), was developed to overcome resistance to cisplatin (CDDP). This study aimed to assess the cytotoxicity of 4M-PzPt against a CDDP-resistant cell line, H4-II-E/CDDP, and compare the intracellular accumulation of CDDP and 4M-PzPt. H4-II-E and H4-II-E/CDDP displayed similar sensitivity to 4M-PzPt; however, the sensitivity of H4-II-E/CDDP to CDDP was approximately 19-fold lower than that of H4-II-E. The difference in the sensitivity to both platinum complexes corresponded with the difference in the amount of intracellular platinum accumulation after exposure to CDDP or 4M-PzPt in both cell lines. In H4-II-E, HepG2, and HuH-7 cells, the intracellular uptake of CDDP and 4M-PzPt occurred via active transport and passive transport. Results of co-exposure with the transport inhibitors ouabain, tetraethylammonium, and cimetidine indicated that the intracellular uptake of CDDP was dependent on Na(+)/K(+)-ATPase and that of 4M-PzPt was dependent on organic cation transporters (OCTs), probably OCT1. This study suggested that 4M-PzPt could inhibit the growth of a CDDP-resistant tumor via an intracellular uptake mechanism different from that of CDDP.
... CLs formed preferentially between guanine residues separated by one or more intervening base pairs. The distortions induced in DNA conformation by these long range CLs are different from those induced by the CLs of cisplatin and extend over more base pairs [21][22][23] . Directional isomers, where interstrand CLs are formed in the "normal" 5′ -> 5′ direction as well as the converse 3′ -> 3′ are also formed 23 . ...
... The distortions induced in DNA conformation by these long range CLs are different from those induced by the CLs of cisplatin and extend over more base pairs [21][22][23] . Directional isomers, where interstrand CLs are formed in the "normal" 5′ -> 5′ direction as well as the converse 3′ -> 3′ are also formed 23 . Thus, we examined whether the structurally distinct family of BBR3464-DNA adducts perturb the кB site-NF-κ B protein interaction and compared the results with those of identical experiments performed with cisplatin or transplatin. ...
Nuclear DNA is the target responsible for anticancer activity of platinum anticancer drugs. Their activity is mediated by altered signals related to programmed cell death and the activation of various signaling pathways. An example is activation of nuclear factor kappaB (NF-κB). Binding of NF-κB proteins to their consensus sequences in DNA (κB sites) is the key biochemical activity responsible for the biological functions of NF-κB. Using gel-mobility-shift assays and surface plasmon resonance spectroscopy we examined the interactions of NF-κB proteins with oligodeoxyribonucleotide duplexes containing κB site damaged by DNA adducts of three platinum complexes. These complexes markedly differed in their toxic effects in tumor cells and comprised highly cytotoxic trinuclear platinum(II) complex BBR3464, less cytotoxic conventional cisplatin and ineffective transplatin. The results indicate that structurally different DNA adducts of these platinum complexes exhibit a different efficiency to affect the affinity of the platinated DNA (κB sites) to NF-κB proteins. Our results support the hypothesis that structural perturbations induced in DNA by platinum(II) complexes correlate with their higher efficiency to inhibit binding of NF-κB proteins to their κB sites and cytotoxicity as well. However, the full generalization of this hypothesis will require to evaluate a larger series of platinum(II) complexes.
