An Overview of Altered Pathways Associated with Sensitivity to Platinum-Based Chemotherapy in Neuroendocrine Tumors: Strengths and Prospects.

Neuroendocrine neoplasms (NENs) are a diverse group of malignancies with a shared phenotype but varying prognosis and response to current treatments. Based on their morphological features and rate of proliferation, NENs can be classified into two main groups with a distinct clinical behavior and response to treatment: (i) well-differentiated neuroendocrine tumors (NETs) or carcinoids (with a low proliferation rate), and (ii) poorly differentiated small- or large-cell neuroendocrine carcinomas (NECs) (with a high proliferation rate). For certain NENs (such as pancreatic tumors, higher-grade tumors, and those with DNA damage repair defects), chemotherapy is the main therapeutic approach. Among the different chemotherapic agents, cisplatin and carboplatin, in combination with etoposide, have shown the greatest efficacy in treating NECs compared to NETs. The cytotoxic effects of cisplatin and carboplatin are primarily due to their binding to DNA, which interferes with normal DNA transcription and/or replication. Consistent with this, NECs, which often have mutations in pathways involved in DNA repair (such as Rb, MDM2, BRCA, and PTEN), have a high response to platinum-based chemotherapy. Identifying mutations that affect molecular pathways involved in the initiation and progression of NENs can be crucial in predicting the response to platinum chemotherapy. This review aims to highlight targetable mutations that could serve as predictors of therapeutic response to platinum-based chemotherapy in NENs.

Hard/soft selectivity in ligand substitution reactions of beta-diketonate platinum(II) complexes.

The reactivity of platinum(II) complexes of the type [PtCl(O,O-acac)(L)] (1) and [Pt(O,O-acac)(gamma-acac)(L)] (2) (L = DMSO, a; DMS, b), with a range of hard and soft nucleophiles such as dimethylsulfide (DMS, b), triphenylphosphine, (PPh3, c), ethylene (eta2-C2H4, d), carbon monoxide (CO, e), pyridine (py, f), and guanosine (Guo, g) has been investigated. Interestingly, the complexes 1a and 1b undergo selective substitution of the chloro or sulfur ligand depending on the hard/soft character of the incoming nucleophile. The soft incoming ligand replaces the softer one and the hard ligand replaces the harder one, giving [PtCl(O,O'-acac)(L)] complexes (1b, 1c, 1d and 1e in the reaction of 1a with L = DMS, PPh3, eta2-C2H4, CO, respectively), and [Pt(O,O'-acac)(DMSO)(L')] (3f, 3g) and [Pt(O,O'-acac)(DMS)(L')] (4f, 4g) species in the reaction of 1a and 1b with L' = py and guo, respectively. In the cases of 2a and 2b complexes, where the pi-bonded acac (gamma-acac) replaces the chloro ligand, only in the presence of an incoming soft nucleophile substituting the soft sulfur ligand the reaction occurs. Equilibrium constants for the substitution reactions were measured by 1H NMR spectroscopy. Variable temperature 1H NMR spectroscopy studies, performed for the reaction of 1a and 2a complexes with DMS, revealed that the selective substitution of DMSO with DMS takes place in both cases, according to a second-order kinetic law. The calculated values of DeltaH++ and DeltaS++ are consistent with an associative mechanism. NMR spectroscopic characterization (1H, 13C, 195Pt, 31P) for the complexes and crystal structures of isolated complexes ([PtCl(O,O'-acac)(L)] (1) and [Pt(O,O'-acac)(gamma-acac)(L)] (2), L = DMSO, 1a and 2a; L = DMS, 1b and 2b; L = PPh3, 1c and 2c) are herein reported and discussed.

New mononuclear and homodinuclear Pt(ii) complexes with heterocyclic nitrogen chelates: synthesis, characterization, intercalating ability and in vitro cytotoxic activity evaluation.

A series of new mononuclear and dinuclear platinum(ii) compounds based on two bipyridyl systems, linked by an alkyl chain {1,2-bis[4-(4'-methyl-2,2'-bipyridinyl)]ethane, L2, (a), and 1,6-bis[4-(4'-methyl-2,2'-bipyridinyl)]hexane, L6, (b)} have been synthesized and characterized by IR and multinuclear and multidimensional NMR spectroscopy. The coordination sphere of the complexes, designed to give intercalating and/or covalent interactions with DNA, is completed only by exchangeable (Cl(-), I(-) or H(2)O) and/or not leaving (chelate ethylenediamine, en) saturating ligands. Quenching of the DNA-ethidium fluorescence was performed in order to verify the intercalating capability of the water soluble compounds. Furthermore, the in vitro cytotoxicity of all water soluble complexes has been assessed with respect to cisplatin on platinum-sensitive human endometrium (HeLa) and platinum-resistant human breast (MCF-7) cancer cell lines.

Highly selective metal mediated ortho-alkylation of phenol. First platinum containing organometallic chromane analogues.

We were able, for the first time, to synthesize and characterize Pt derivatives with a structural shape similar to vitamin E, having a metalla-chromane core. The formation reaction mechanism includes an unexpected highly selective ortho aromatic electrophilic substitution on phenol, operated by [PtCl(eta(1)-C(2)H(4)OR)(N-N)], R = Me or Ph, and a final cyclization step. The X-ray structure of one of the new metalla-chromane complexes [Pt(EtPh)(phen)],1a, (EtPh = 2-(ethan-2'-yl-kC(1))-1-phenolato-k0(1), phen = 1,10-phenanthroline) is reported. Cytotoxicity and Pt uptake measurements, performed on HeLa cancer cells, show an interesting structure-activity correlation for the new metalla-chromane analogues 1a and [Pt(MeOEtPh)(phen)], 1b, (MeOEtPh = 2-(ethan-2'-yl-kC(1))-4-(methoxy)-1-phenolato-k0(1)), being the structurally closest to vitamin E and also the most active.

New platinum(II) complexes containing both an O,O'-chelated acetylacetonate ligand and a sulfur ligand in the platinum coordination sphere induce apoptosis in HeLa cervical carcinoma cells.

We report the cytotoxic effects obtained in HeLa cells of three newly synthesized platinum complexes containing both an O,O'-chelated acetylacetonate ligand and a sulfur ligand in the platinum coordination sphere, which show, by (1)H NMR, negligible reactivity with purine bases. These compounds induce cell death with [Pt(O,O'-acac)(gamma-acac)(DMS)] being the most effective (IC(50)=0.98+/-0.056 and 1.82+/-0.023 microM for [Pt(O,O'-acac)(gamma-acac)(DMS)] and cisplatin, respectively). About 50% of cells died after 5h treatment with 100 microM [Pt(O,O'-acac)(gamma-acac)(DMS)] whilst a 16 h incubation was required to get the same results using 100 microM cisplatin. Cellular accumulation measurements, after treatment with equimolar drug concentrations, indicated the major lipophilicity and cellular uptake of the new compounds. While the cytotoxicity of cisplatin was due to both intracellular accumulation and DNA binding, that of [Pt(O,O'-acac)(gamma-acac)(DMS)] was associated with intracellular Pt accumulation only, since it has low reactivity to DNA in intact cells and in vitro. The reaction of the new complexes with guanosine and 5'-GMP was negligible, whereas the L-methionine instantly reacted with the initial Pt complexes. Both cisplatin and [Pt(O,O'-acac)(gamma-acac)(DMS)] induced apoptosis in HeLa cells. [Pt(O,O'-acac)(gamma-acac)(DMS)] provoked the early signs of apoptosis induction (cleavage of PARP and activation of caspases-9, -3 and -7) only 1h after addition of the drug. However, in cisplatin-treated cells, cleavage of PARP was seen after 9h with activation of caspases also proceeding more slowly. In conclusion, these results indicate that the newly synthesized platinum(II) complexes have high and rapid cytotoxic activity in vitro, and suggest that DNA may not be their primary target.

New water-soluble platinum(II) phenanthroline complexes tested as cisplatin analogues: First-time comparison of cytotoxic activity between analogous four- and five-coordinate species.

Four- and five-coordinate platinum(II) complexes, cis-[PtCl2(A2)] (1) and [PtCl2(A2)(eta2-ethylene)] (2) {A2 = 4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BPS (mixture of isomers) (a); 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline disulfonic acid disodium salt, BCS (mixture of isomers) (b)} have been synthesized and characterized by 1H, 13C, and 195Pt NMR spectroscopy. The stability and high water solubility of complexes 1a, 1b and 2b, due to the presence of the polar SO3- groups on the ligands skeleton, allowed to test their in vitro cytotoxicity on HeLa tumour cells in a wide range of drug concentration. At low and medium incubation doses (<200 microM) 1a, 1b and 2b all showed similar in vitro cytotoxicity, negligible or much lower with respect to cisplatin. At doses higher than 200 microM their activity increased and 1b, the most active among the new complexes, exhibited a cytotoxicity comparable, although still lower, with respect to cisplatin. GFAAS Platinum analytical data showed that the tested compounds 1a, 1b and 2b, although carrying sulfonate charged groups, may undergo cellular uptake, which, in the case of 1b and 2b, is even higher with respect to cisplatin. Furthermore, in the case of 1b and 2b it has been possible to compare, for the first time, the cytotoxic activity for square-planar four-coordinate and trigonal-bipyramidal five-coordinate platinum(II) complexes having the same carrier ligand. The tendency of the five-coordinate species 2b to give at longer incubation time similar cytotoxicity with respect to the square-planar compound 1b suggests a possible use of the trigonal-bipyramidal five-coordinate complexes as prodrugs.

Differential response of normal, dedifferentiated and transformed thyroid cell lines to cisplatin treatment.

The effects of cisplatin (cisPt) on the extra cellular signal-regulated kinase (ERK) and the protein kinase B (PKB/Akt), known to play important roles in promoting cell survival and in down regulating apoptosis, were investigated in thyroid cell lines. The cytotoxic effect of cisPt was highest in normal PC-Cl3 cells, intermediate in dedifferentiated PC-E1A and PC-raf cells and lowest in fully transformed and tumorigenic PC-E1Araf cells. CisPt provoked ERK phosphorylation; such phosphorylation was unaltered by Gö6976, a conventional PKC inhibitor, whilst blocked by low doses (0.1 microM) or high doses (10 microM) of GF109203X, an inhibitor of all PKC isozymes, in PC-Cl3 and in PC-E1Araf cells, respectively. In PC-E1Araf, but not in PC-Cl3 cells, the cisPt-provoked ERK phosphorylation was also blocked by a myristoylated PKC-zeta pseudo substrate peptide (PS-zeta). The cytotoxic effects of cisPt increased when cells were pre-incubated with the mitogen-activated protein kinase (MEK) inhibitor PD98059. CisPt provoked the phosphorylation of PKB/Akt and this effect was blocked by LY294002, a PI3K inhibitor. In PC-Cl3 cells pre-incubated with LY294002 the effects of cisPt on ERK phosphorylation and cell mortality resulted unaffected; conversely, LY294002 reduced the ERK phosphorylation and increased cisPt cytotoxity of in PC-E1Araf cells. Furthermore, in PC-E1Araf cells pre-incubated with LY294002 and PS-zeta ERK phosphorylation was abolished and cisPt cytotoxicity was highest. Altogether results highlight a role for PKCs in the upstream regulation of ERK pathway facing the cell response to cisPt treatments. Understanding the mechanisms by which cells process cisPt provides important insights for designing more efficient platinum-based drugs.