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Structure-activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells.

ABSTRACT: As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of [Ti(4)(maltolato)(8)(mu-O)(4)], (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(3) and CO(2)CH(2)CH(3)), and three water-soluble titanocene-amino acid complexes-[Cp(2)Ti(aa)(2)]Cl(2) (aa = L: -cysteine, L: -methionine, and D: -penicillamine)-on the human colon adenocarcinoma cell line, HT-29. The capacity of [Ti(4)(maltolato)(8)(mu-O)(4)] to donate Ti(IV) to human apo-transferrin and its hydrolytic stability have been investigated and compared to the previously reported data on modified titanocenes with either hydrophilic ancillary ligands or the functionalized cyclopentadienyl ligands. Notably, the titanium-maltolato complex does not transfer Ti(VI) to human apo-transferrin at any time within the first seven days of its interaction, demonstrating the inert character of this species. Stability studies on these complexes have shown that titanocene complexes decompose at physiological pH while the [Ti(4)(maltolato)(8)(mu-O)(4)] complex is stable at this pH without any notable decomposition for a period of ten days. The antitumor activity of these complexes against colon cancer HT-29 cells was determined using an MTT cell viability assay at 72 and 96 h. The titanocene-amino acid and the (Cp-R)(2)TiCl(2)/(Cp-R)CpTiCl(2) (R = CO(2)CH(3)) complexes were not biologically active when human transferrin was absent; they also were inactive when human transferrin was present at dose-equivalent concentrations. (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(2)CH(3)) showed cytotoxic activity in HT-29 cells comparable to that which is displayed by titanocene dichloride. The titanium-maltolato complex had higher levels of cytotoxic activity than any other titanocene complex investigated. Transferrin may be important in protecting the titanium center from hydrolysis, but this may be achieved by selecting ligands that could result in hydrolytically stable, yet active, complexes.

SUBMITTER: Hernandez R

PROVIDER: S-EPMC4461444 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Structure-activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells.

Hernández Ramón R Lamboy José J Gao Li Ming LM Matta Jaime J Román Félix R FR Meléndez Enrique E

Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 20080221 5

As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of [Ti(4)(maltolato)(8)(mu-O)(4)], (Cp-R)(2)TiCl(2) and (Cp-R)CpTiCl(2) (R = CO(2)CH(3) and CO(2)CH(2)CH(3)), and three water-soluble titanocene-amino acid complexes-[Cp(2)Ti(aa)(2)]Cl(2) (aa = L: -cysteine, L: -methionine, and D: -penicillamine)-on the human colon adenocarcinoma cell line, HT-29. The capacity of [Ti(4)(maltolato)(8)(mu-O)(4)] to donate Ti(IV) to human apo- ...[more]

PMID: 18288505

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Project description:5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that has been reported to be effective against different cancer cells. Its active compound is melittin, a positively charged amphipathic peptide that interacts with the phospholipids of the cell membrane, forming pores that enable the internalization of small molecules with cytotoxic activities,. and consequently, causing cell death. Some central nervous system (CNS) drugs have recently demonstrated great anti-cancer potential, both in vitro, in vivo and in clinical trials, being promising candidates for drug repurposing in oncology. The present work evaluated the anti-cancer efficacy of honeybee venom in combination with chemotherapeutic or CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. The chemical characterization of a Portuguese sample of honeybee venom was done by LC-DAD-ESI/MSn analysis. For single treatments, cells were incubated with increasing concentrations of bee venom. For combination treatments, increasing concentrations of bee venom were first combined with the half-maximal inhibitory concentration (IC50) of 5-FU and DOX, in HT-29 and MCF-7 cells, respectively. Cells were also treated with increasing concentrations of bee venom in combination with the IC50 value of four CNS drugs (fluphenazine, fluoxetine, sertraline and thioridazine). Cytotoxicity was evaluated by MTT and SRB assays. The combination index (CI) value was calculated using CompuSyn software, based on the Chou-Talalay method. Synergy scores of different reference models (HSA, Loewe, ZIP and Bliss) were also calculated using SynergyFinder. The results demonstrate that honeybee venom is active against HT-29 colon and MCF-7 breast cancer cells, having better anti-tumour activity in MCF-7 cells. It was found that bee venom combined with 5-FU and fluphenazine in HT-29 cells resulted in less cytotoxic effects compared to the co-treatment of fluoxetine, sertraline and thioridazine plus bee venom, which resulted in less than 15% of viable cells for the whole range of concentrations. The combination of MCF-7 cells with repurposed drugs plus honeybee venom resulted in better anti-cancer efficacies than with DOX, notably for lower concentrations. A combination of fluoxetine and thioridazine plus honeybee venom resulted in less than 40% of viable cells for all ranges of concentrations. These results support that the combination of honeybee venom with repurposed drugs and chemotherapeutic agents can help improve their anti-cancer activity, especially for lower concentrations, in both cell lines. Overall, the present study corroborates the enormous bioactive potential of honeybee venom for colon and breast cancer treatments, both alone and in combination with chemotherapy or repurposed drugs.

Project description:The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion reveals a difference in Ti(IV) coordination versus iron(III), the metal endogenously delivered by the protein to cells. This finding enriches our bioinspired drug design strategy for Ti(IV)-based anticancer therapeutics, which applies a family of Fe(III) chelators termed chemical transferrin mimetic (cTfm) ligands to inhibit Fe bioavailability in cancer cells. Deferasirox, a drug used for iron overload disease, is a cTfm ligand that models STf coordination to Fe(III), favoring Fe(III) binding versus Ti(IV). This metal affinity preference drives deferasirox to facilitate the release of cytotoxic Ti(IV) intracellularly in exchange for Fe(III). An aqueous speciation study performed by potentiometric titration from pH 4 to 8 with micromolar levels of Ti(IV) deferasirox at a 1:2 ratio reveals exclusively Ti(deferasirox)2 in solution. The predominant complex at pH 7.4, [Ti(deferasirox)2]2-, exhibits the one of the highest aqueous stabilities observed for a potent cytotoxic Ti(IV) species, demonstrating little dissociation even after 1 month in cell culture media. UV-vis and 1H NMR studies show that the stability is unaffected by the presence of biomolecular Ti(IV) binders such as citrate, STf, and albumin, which have been shown to induce dissociation or regulate cellular uptake and can alter the activity of other antiproliferative Ti(IV) complexes. Kinetic studies on [Ti(deferasirox)2]2- transmetalation with Fe(III) show that a labile Fe(III) source is required to induce this process. The initial step of this process occurs on the time scale of minutes, and equilibrium for the complete transmetalation is reached on a time scale of hours to a day. This work reveals a mechanism to deliver Ti(IV) compounds into cells and trigger Ti(IV) release by a labile Fe(III) species. Cellular studies including other cTfm ligands confirm the Fe(III) depletion mechanism of these compounds and show their ability to induce early and late apoptosis.

Project description:Resistance of tumor cells to chemotherapy, such as 5?fluorouracil (5?FU), is an obstacle for successful treatment of cancer. As a follow?up of a previous study we have investigated the effect of conditioned media (CM) from macrophages of M1 or M2 phenotypes on 5?FU cytotoxicity on the colon cancer cell lines HT?29 and CACO?2. HT?29 cells, but not CACO?2 cells, having been treated with a combination of M1 CM and 5?FU recovered their cell growth to a much larger extent compared to cells having been treated with 5?FU alone when further cultured for 7 days in fresh media. M1 CM treatment of HT?29, but not CACO?2 cells, induced cell cycle arrest in the G0/G1 and G2/M phases. 5?FU treatment induced accumulation of cells in S?phase in both HT?29 and CACO?2 cells. This accumulation of cells in S?phase was attenuated by combined M1 CM and 5?FU treatment in HT?29 cells, but not in CACO?2 cells. The mRNA expression of cell cycle regulatory proteins and 5?FU metabolic enzymes were analyzed in an attempt to find possible mechanisms for the M1 CM induced attenuation of 5?FU cytotoxicity in HT?29. Thymidylate synthetase (TS) and thymidine phosphorylase (TP) were found to be substantially downregulated and upregulated, respectively, in HT?29 cells treated with M1 CM, making them unlikely as mediators of reduced 5?FU cytotoxicity. Among cell cycle regulating proteins, p21 was induced in HT?29 cells, but not in CACO?2 cells, in response to M1 CM treatment. However, small interfering RNA (siRNA) knockdown of p21 had no effect on the M1 CM induced cell cycle arrest seen in HT?29 and neither did it change the growth recovery after combined treatment of HT?29 cells with M1 CM and 5?FU. In conclusion, treatment of HT?29 cells with M1 CM reduces the cytotoxic effect of 5?FU and this is mediated by a M1 CM induced cell cycle arrest in the G0/G1 and G2/M phases. So far, we lack an explanation why this action is absent in the CACO?2 cells. The current findings may be important for optimization of chemotherapy in colon cancer.

Project description:In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\RXR ligand binding domain of PRI-2205 may, in part, explain its very low toxicity with sustained anticancer activity.

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Dataset Information

Structure-activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells.

Publications

Structure-activity studies of Ti(IV) complexes: aqueous stability and cytotoxic properties in colon cancer HT-29 cells.

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