Inside the biochemical pathways of thymidylate synthase perturbed by anticancer drugs: Novel strategies to overcome cancer chemoresistance

Taddia, Laura; D’Arca, Domenico; Ferrari, Stefania; Chiara, María Luisa Dalla; Severi, Leda; Ponterini, Glauco; Assaraf, Yahuda G.; Marverti, Gaetano; Costi, Maria Paola

doi:10.1016/j.drup.2015.10.003

Cited by 55 publications

(53 citation statements)

References 293 publications

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“…Currently, surgery, radiation, chemotherapy and targeted therapy are used in lung cancer treatment [ 7 , 8 , 9 , 10 ]. However, resistance to anticancer drugs has been observed and normal cells may also be destroyed by the side effects of anticancer drugs [ 11 , 12 ]. Therefore, it is necessary to study and develop more effective and low-toxicity natural anticancer drugs.…”

Section: Introductionmentioning

confidence: 99%

A Purified Serine Protease from Nereis virens and Its Impaction of Apoptosis on Human Lung Cancer Cells

et al. 2017

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Nereis active protease (NAP) is a novel fibrinolytic active serine protease from the polychaete Nereis virens. In this study, NAP was purified from Nereis virens and the effects of NAP on human lung cancer cells were investigated. Our results indicated that NAP inhibited the proliferation and induced apoptosis of H1299 cells in a time- and dose-dependent manner. The loss of mitochondrial membrane potential, the activation of Bax and cleaved-caspase 3/9, the release of cytochrome C, and the suppression of Bcl-2 and poly-ADP ribose polymerase were observed in NAP-treated H1299 cells by flow cytometry and Western blotting. Moreover, the expression levels of Bax and Bcl-2 mRNA were determined by real-time quantitative polymerase chain reaction and the Bax/Bcl-2 expression ratio was increased in the NAP-treated cell lines. The results indicated that NAP-induced apoptosis may be related to mitochondria mediated apoptosis and occurs through caspase-dependent pathways. Then, the effects of NAP on tumor growth in animal models were observed, where 5 or 10 mg/kg of NAP noticeably reduced tumor volume and weight and increased apoptosis as determined by Western blotting when compared to the negative control group. Therefore, our findings suggest that NAP could be a hopeful anticancer medicine for its propensity to inhibit growth and induce of apoptosis in human lung cancer cells.

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Section: Introductionmentioning

confidence: 99%

A Purified Serine Protease from Nereis virens and Its Impaction of Apoptosis on Human Lung Cancer Cells

et al. 2017

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“…Currently, chemotherapy is the most common method used to eliminate cancer cells, prevent cancer recurrence, control cancer by slowing cell growth, and reduce symptoms [2]. However, healthy cells may be damaged by the many side effects of anticancer drugs, and resistance to anticancer drugs has been observed [3]. Therefore, substantial attention is being paid to identifying anticancer drugs with high efficiency and low toxicity from natural sources [4].…”

Section: Introductionmentioning

confidence: 99%

Anticancer Activity of a Hexapeptide from Skate (Raja porosa) Cartilage Protein Hydrolysate in HeLa Cells

Pan

Zhao

et al. 2016

Marine Drugs

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In this study, the hexapeptide Phe-Ile-Met-Gly-Pro-Tyr (FIMGPY), which has a molecular weight of 726.9 Da, was separated from skate (Raja porosa) cartilage protein hydrolysate using ultrafiltration and chromatographic methods, and its anticancer activity was evaluated in HeLa cells. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay indicated that FIMGPY exhibited high, dose-dependent anti-proliferation activities in HeLa cells with an IC50 of 4.81 mg/mL. Acridine orange/ethidium bromide (AO/EB) fluorescence staining and flow cytometry methods confirmed that FIMGPY could inhibit HeLa cell proliferation by inducing apoptosis. Western blot assay revealed that the Bax/Bcl-2 ratio and relative intensity of caspase-3 in HeLa cells treated with 7-mg/mL FIMGPY were 2.63 and 1.83, respectively, significantly higher than those of the blank control (p < 0.01). Thus, FIMGPY could induce apoptosis by upregulating the Bax/Bcl-2 ratio and caspase-3 activation. Using a DNA ladder method further confirmed that the anti-proliferation activity of FIMGPY was attributable to its role in inducing apoptosis. These results suggest that FIMGPY from skate cartilage protein hydrolysate may have applications as functional foods and nutraceuticals for the treatment and prevention of cancer.

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“…Candidate pharmacogenes for this action include the enzymes involved in the DNA repair mechanisms and the cell cycle control such as TOP2A, MLH1, MSH2, TP53, and ERCC2 genes [36]. Two enzymes of the folate cycle, TS and DHFR, are also essential proteins for a normal cell cycle occurrence and DNA synthesis and ensure the correct substitution of damaged DNA after injury by chemotherapeutics [37]. In this work, the down-regulation of the TS protein expression by some complexes, especially Pd(phen), might reflect a characteristic similar to those observed with other DNA damaging agents [38].…”

Section: Discussionmentioning

confidence: 99%

The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines

Marverti

Gozzi

Lauriola

et al. 2019

IJMS

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Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Thus, new therapeutical agents are needed. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell lines and their resistant counterparts. The compounds were the complexes of Pt(II) or Pd(II) with bipyridyl (bipy) and phenanthrolyl (phen) and with four different thiourea ancillary ligands. Within each of the four series of complexes characterized by the same thiourea ligand, the Pd(phen) drugs invariably showed the highest anti-proliferative efficacy. This paralleled both a higher intracellular drug accumulation and a more efficient DNA intercalation than all the other metal-bidentate ligand combinations. The consequent inhibition of topoisomerase II activity led to the greatest inhibition of DNA metabolism, evidenced by the inhibition of the expression of the folate cycle enzymes and a marked perturbation of cell-cycle distribution in both cell lines. These findings indicate that the particular interaction of Pd(II) with phenanthroline confers the best pharmacokinetic and pharmacodynamic properties that make this class of DNA intercalators remarkable inhibitors, even of the resistant cell growth.

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Inside the biochemical pathways of thymidylate synthase perturbed by anticancer drugs: Novel strategies to overcome cancer chemoresistance

Cited by 55 publications

References 293 publications

A Purified Serine Protease from Nereis virens and Its Impaction of Apoptosis on Human Lung Cancer Cells

A Purified Serine Protease from Nereis virens and Its Impaction of Apoptosis on Human Lung Cancer Cells

Anticancer Activity of a Hexapeptide from Skate (Raja porosa) Cartilage Protein Hydrolysate in HeLa Cells

The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines

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