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Complexes [In(L1)Cl(H2O)] (1), [In(L2)Cl(H2O)]·3H2O (2), [In(L3)Cl(H2O)]·H2O (3), [In(L4)Cl(H2O)] (4), and [In(L5)Cl(H2O)] (5) with 2,6-diformylpyridine-bis(benzoylhydrazone) (H2L1), 2,6-diformylpyridine-bis(para-chloro-benzoylhydrazone) (H2L2), 2,6-diformylpyridine-bis(para-toluyl-benzoylhydrazone) (H2L3), 2,6-diacetylpyridine-bis(semicarbazone) (H2L4), and 2,6-diacetylpyridine-bis(thiosemicarbazone) (H2L5) were synthesized. The cytotoxic effects of selected compounds were tested on MCF-7 (estrogen-dependent mammary adenocarcinoma), MDA-MB-231 (triple-negative mammary adenocarcinoma), and MRC-5 (healthy human lung fibroblast) cells. H2L4, H2L5, and complexes 1, 3, 4, and 5 were cytotoxic against MCF-7 and MDA-MB-231 cells in a dose-dependent way, presenting IC50 values in the micromolar range. 1, 3, 4, and 5 were exposed to neutron activation to produce their 114mIn(III) analogs *1, *3, *4, and *5. Complex *3 was 13-fold more potent than its non-radioactive counterpart against both tumor cell lineages and complex *5 was 11-fold more potent than complex 5 against MCF-7 cells and 4-fold more potent than complex 5 against MDA-MB-231 cells. Radiotherapy with gamma radiation from a 60Co source combined with the treatment with complexes 1, 3, 4, and 5 improved the efficacy of radiotherapeutic doses in the range used for hypo-fractionated radiotherapy. Combined treatment with increasing concentrations of non-radioactive compounds and 1 Gy caused a 2.27- to 4.49-fold increase in the radiation enhancement factor (REF) (REF = % cell death due to combined therapy/% cell death due to radiation monotherapy) against MCF-7 cells. Interestingly, combination therapy was even more beneficial for treating triple-negative MDA-MB-231 tumor cells, with REF ranging from 5.27 to 7.53. The results demonstrate that the indium(III) complexes under study behave as potential multifunctional agents for treating breast cancer, due to their cytotoxic activities, radiosensitizer effects, and the possible ability of the 114mIn derivatives to be employed in targeted radionuclide therapy. [ABSTRACT FROM AUTHOR]

Aim: Evaluation of the biocompatibility and radiosensitizer potential of citrate-coated cobalt (cit-CF) and nickel (cit-NF) ferrite nanoparticles (NPs). Materials & methods: Normal fibroblast and breast cancer cells were treated with different concentrations of citrate-coated ferrite NPs (cit-NPs) and irradiated with a cobalt-60 source at doses of 1 and 3 Gy. After 24 h, cell metabolism, morphology alterations and nanoparticle uptake were evaluated. Results: Cit-CF and cit-NF NPs showed no toxicity to normal cells up to 250 and 100 μg.ml-1, respectively. Combination of cit-NP and ionizing radiation resulted in up to fivefold increase in the radiation therapeutic efficacy against breast cancer cells. Conclusion: Cit-CF and cit-NF NPs are suitable candidates for application as breast cancer cell radiosensitizers. [ABSTRACT FROM AUTHOR]

Breast cancer continues to be the major cause of cancer death among women. The high genetic heterogeneity and chemoresistant phenotypes of breast tumors require the search for new compounds to expand the options for the treatment of this disease. Kaurenoic acid (KA) is an ent‐kaurane type‐diterpene with cytotoxic and genotoxic effects against gastric and cervical cancer cells. In the present study, we report the antiproliferative effects of KA in the breast tumoral cell line MCF‐7 and the normal breast counterpart MCF‐10 A. The long‐term cytotoxic effects of KA were observed by the reduction of survival fraction at 50 and 100 μM. At these concentrations, the treatment with KA increased the extension of DNA damage followed by G1 cell cycle phase accumulation and induction of apoptosis in both cell lines. Taken together, the results contained herein support the promising antiproliferative effects of KA. [ABSTRACT FROM AUTHOR]

In(iii) complexes [In(2Ac4oClPh)2]NO3 (1) and [In(2Ac4pFPh)2]NO3·1.5H2O (2) were obtained with N(4)-ortho-chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4oClPh) and N(4)-para-fluorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pFPh). Neutron activation of complexes (1) and (2), and of previously prepared [In(2Ac4oClPh)Cl2(MeOH)] (3) and [In(2Ac4pFPh)Cl2(MeOH)] (4) resulted in the formation of 114mIn/115mIn analogues (*1–*4). The cytotoxic activities of the compounds under study were investigated on MCF-7 breast cancer cells as well as against non-malignant MRC-5 fibroblast cells. Upon coordination to In(iii) the cytotoxicity against MCF-7 cells significantly increased in complexes (1–4), suggesting that complexation was a good strategy to improve the cytotoxic effect. While both non-radioactive and radioactive In(iii) salts were inactive against MCF-7 cells, the radioactive complexes (*1–*4) proved to be 102 to 104 times more potent than the non-radioactive analogues (1–4). For the non-radioactive In(iii) complexes (1–4) the selectivity indexes (SI), defined as IC50 MRC-5/IC50 MCF-7, were SI = 0.07–0.36, while high values of SI were found for the radioactive In(iii) analogues (*1–*4), SI = 46–4716, indicating that irradiation represented an interesting strategy for increasing the selectivity. Since cytotoxicity was evaluated following 48 h of treatment and 72 h after neutron activation, the observed cytotoxic effects were attributed mainly to 114mIn, the contribution of the 115mIn (t1/2 = 4.5 h) isomer being considered irrelevant. Complexes (*1–*4) induced higher levels of intracellular ROS in MCF-7 cells in comparison to the parent compounds. The results suggest that 114mIn complexes with thiosemicarbazones might show potential for application as radiopharmaceuticals for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Abstract In this study, ent -kaurenoic acid derivatives were obtained by microbial transformation methodologies and tested against breast cancer cell lines (MCF-7). A multivariate quantitative-structure activity relationship (QSAR) analysis was performed taking into account both microbial transformation derivatives and other analogues previously reported in literature to give some insight into the main features behind the cytotoxic activity displayed by kaurane-type diterpenes against MCF-7 cells. The partial least square regression (PLS) method was employed in the training set and the best PLS model was built with a factor describing 69.92% of variance and three descriptors (log P , ε HOMO and ε HOMO–1) selected by the Ordered Predictors Selection (OPS) algorithm. The QSAR model provided reasonable regression (Q 2 = 0.64, R 2 = 0.72, SEC = 0.29 and SEV = 0.33). The model was validated by leave- N -out cross-validation, y-randomization and external validation (R 2 pred = 0.89 and SEP = 0.27). The selected descriptors indicated that the activity was mainly related to electronic parameters (HOMO and HOMO-1 molecular orbital energies), as well as to log P. These findings suggest that higher activity values are directly related with both higher log P and frontier orbital energy values. The positive relationship between these orbitals and the activity suggests that the ent -kaurenoic acid analogues interaction with the target involves charge displacement, which is entirely consistent with the literature. Based on these findings, three compounds were proposed and one of them was synthesized and tested. The experimental result confirmed the activity predicted by the model. Graphical abstract According to QSAR analysis, the activity of kaurenoic acid derivatives against MCF-7 breast cancer cells is related to the log P and to the energies of the HOMO and HOMO–1. Image 1 Highlights • Kaurenoic acid derivatives interact with MCF7 cells by charge transfer mechanism. • Higher activity against MCF-7 cells is related with both log P and frontier orbitals. • Kaurenoic acid derivatives were proposed to be synthetized based on the QSAR model. [ABSTRACT FROM AUTHOR]

Abstract: N 4-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N 4-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N 4-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N 4-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N 4-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO2Ph, H2Ac4mNO2Ph, H2Ac4pNO2Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC50: MCF-7, 52–0.16nM; T98G, 140–1.0nM; U87, 160–1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10−5 M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization. [Copyright &y& Elsevier]