Collateral sensitivity to novel thymidylate synthase inhibitors correlates with folate cycle enzymes impairment in cisplatin-resistant human ovarian cancer cells

Marverti, Gaetano; Ligabue, Alessio; Paglietti, Giuseppe; Corona, Paola; Piras, Sandra; Vitale, Gabriella; Guerrieri, Davide; Luciani, Rosaria; Costi, Maria Paola; Frassineti, Chiara; Moruzzi, Maria Stella

doi:10.1016/j.ejphar.2009.04.062

Cited by 29 publications

(40 citation statements)

References 40 publications

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“…5C), these were determined under the same experimental conditions. The total hTS protein level was increased by 5-FU exposure in both cell lines, which has been suggested to be due to the formation of the inactive ternary complex hTS-FdUMP-mTHF (45). In contrast, 20 μM LR decreased the total hTS protein level by about 25% in sensitive cells and did not affect the protein level in the resistant cells (Fig.…”

Section: Peptides Inhibit Hts In Ovarian Cancer Cells Without Resultimentioning

confidence: 79%

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

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Guaitoli

Tondi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The undersigned authors note the following: "We wish to bring to your attention an issue regarding our PNAS publication referenced above. Although we cite our earlier PNAS publication (see ref. Figs. 2 and 3 display the UWHBs for Hb β-subunit (pdb.1bz0, chain B) and human cellular prion protein (pdb.1qm0) (12)(13)(14). Within the natural interactive context of the Hb subunit, the UWHBs signal crucial binding regions (24): UWHBs (90, 94), (90, 95) are associated with the β-FG corner involved in the quaternary α1β2 interface; UWHB (5, 9) is adjacent to Glu-6 which in sickle cell anemia mutates to Val-6 and is located at the Val-6-(Phe-85, Leu-88) interface in the deoxyHbS fiber."The following text in the section titled 'Toward a Structural Diagnosis' on page 6449 of our text is similar to the text beginning in the last paragraph on page 2392 in ref. 23:The distribution of proteins according to their average extent of hydrogen bond wrapping and their spatial concentration of structural defects is shown in Fig. 5 (see also ref. 23). The sample of 2,811 PDB proteins is large enough to define a reliable abundance distribution with an inflection point at ρ = 6.20. The integration of the distribution over a ρ-interval gives the fraction of proteins whose ρ lies within that range. Of the 2,811 proteins examined, 2,572 have ρ > 6.20, and none of them is known to yield amyloid aggregation under physiological conditions entailing partial retention of structure. Strikingly, relatively few disease-related amyloidogenic proteins are known in the sparsely populated, underwrapped 3.5 < ρ < 6.20 range, with the cellular prion proteins located at the extreme of the spectrum (3.53 < ρ < 3.72)....The range of H-bond wrapping 3.5 < ρ < 4.6 of 20 sampled PDB membrane proteins has been included in Fig. 5 for comparison. As expected, such proteins do not have the stringent H-bond packing requirements of soluble proteins for their H bonds at the lipid interface. Thus, this comparison becomes suggestive in terms of elucidating the driving factor for aggregation in soluble proteins: Although the UWHB constitutes a structural defect in a soluble protein because of its vulnerability to water attack, it is not a structural defect in a membrane protein. The exposure of the polar amide and carbonyl of the unbound state to a nonpolar phase is thermodynamically unfavorable (22). The virtually identical ρ value for human prion and outer-membrane protein A (Fig. 5) is revealing in this regard.Furthermore, all known amyloidogenic proteins that occur naturally in complexed form have sufficient H-bond wrapping within their respective complexes (ρ value near 6.2). Their amyloidogenic propensity appears only under conditions in which the protein is dissociated from the complex (compare Fig. 5). This finding is corroborated by the following computation. If an intramolecular hydrogen bond is underwrapped within the isolated protein molecule but located at an interface upon complexation, then to determine its extent of wrapping within the complex, we take ...

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Section: Peptides Inhibit Hts In Ovarian Cancer Cells Without Resultimentioning

confidence: 79%

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

Cardinale

Guaitoli

Tondi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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157

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“…It is well known that cDDP arrests the cell cycle in the G 2 /M phase [48] while DENSpm first retards the S phase progression and later increases the sub-G 1 population and/or arrests the cell cycle in G 1 [49], [50], [51], [52]. Thus, both drugs can impair the S phase and moreover have already shown a synergistic cell killing effect when combined with novel folate cycle inhibitors with quinoxaline structure in these ovarian carcinoma cell lines [20], [39]. Our results show that the cell killing resulting from the drug combinations between 5-FU and cDDP or DENSpm is affected by the drug treatment schedule (p<0.05, n = 3, table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Different regulatory mechanisms contributing to this phenomenon have been described in distinct human cell lines. For instance, in human gastrointestinal cell lines (Hutu 80, HT-29 and WIDR), as well as in human ovarian carcinoma cell lines (2008 and C13*), the ternary complex 5-FdUMP-MTF-hTS has increased stability as compared with the non-complexed enzyme, thus increasing up to 6-fold the steady-state expression level of hTS [20], [21]. The increase in protein stability is controlled by the amino-terminus of hTS that contains an intrinsically disordered region essential for ubiquitin-independent degradation by the proteasome and which may be partially buried in the ternary complex [22].…”

Section: Introductionmentioning

confidence: 99%

“…In this study we have investigated the relevance of these proposed mechanisms for hTS regulation and assayed their kinetics during 5-FU treatment in the ovarian cancer cell line 2008 and the corresponding cisplatin resistant- and 5-FU cross-resistant subline C13* that shows higher steady-state expression level of the enzymes of the folate cycle [20]. Despite the constitutively higher levels of TYMS in the C13* cell line, we found no obvious effect on splicing or maturation of TYMS pre-mRNA.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional Activation and Cell Cycle Block Are the Keys for 5-Fluorouracil Induced Up-Regulation of Human Thymidylate Synthase Expression

et al. 2012

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Background5-fluorouracil, a commonly used chemotherapeutic agent, up-regulates expression of human thymidylate synthase (hTS). Several different regulatory mechanisms have been proposed to mediate this up-regulation in distinct cell lines, but their specific contributions in a single cell line have not been investigated to date. We have established the relative contributions of these previously proposed regulatory mechanisms in the ovarian cancer cell line 2008 and the corresponding cisplatin-resistant and 5-FU cross-resistant-subline C13*.Methodology/Principal FindingsUsing RNA polymerase II inhibitor DRB treated cell cultures, we showed that 70–80% of up-regulation of hTS results from transcriptional activation of TYMS mRNA. Moreover, we report that 5-FU compromises the cell cycle by blocking the 2008 and C13* cell lines in the S phase. As previous work has established that TYMS mRNA is synthesized in the S and G1 phase and hTS is localized in the nuclei during S and G2-M phase, the observed cell cycle changes are also expected to affect the intracellular regulation of hTS. Our data also suggest that the inhibition of the catalytic activity of hTS and the up-regulation of the hTS protein level are not causally linked, as the inactivated ternary complex, formed by hTS, deoxyuridine monophosphate and methylenetetrahydrofolate, was detected already 3 hours after 5-FU exposure, whereas substantial increase in global TS levels was detected only after 24 hours.Conclusions/SignificanceAltogether, our data indicate that constitutive TYMS mRNA transcription, cell cycle-induced hTS regulation and hTS enzyme stability are the three key mechanisms responsible for 5-fluorouracil induced up-regulation of human thymidylate synthase expression in the two ovarian cancer cell lines studied. As these three independent regulatory phenomena occur in a precise order, our work provides a feasible rationale for earlier observed synergistic combinations of 5-FU with other drugs and may suggest novel therapeutic strategies.

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“…A variety of mechanisms associated with antioxidant and transporter genes was proposed by the authors [20]. There are also examples of platinum-resistance being associated with collateral sensitivity to anti-folate compounds [21]. …”

Section: Collateral Sensitivity Of Drug Resistant Cell Lines – Are Thmentioning

confidence: 99%

Polo Like Kinase 2 Tumour Suppressor and cancer biomarker: new perspectives on drug sensitivity/resistance in cancer

et al. 2012

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The polo-like kinase PLK2 has recently been identified as a potential theranostic marker in the management of chemotherapy sensitive cancers. The methylation status of the PLK2 CpG island varies with sensitivity to paclitaxel and platinum in ovarian cancer cell lines. Importantly, extrapolation of these in vitro data to the clinical setting confirms that the methylation status of the PLK2 CpG island predicts outcomes in patients treated with carboplatin & paclitaxel chemotherapy. A second cell cycle regulator, p57Kip2, is also subject to epigenetic silencing in carboplatin resistance in vitro and in vivo, emphasising that cell cycle regulators are important determinants of sensitivity to chemotherapeutic agents and providing insights into the phenomenon of collateral drug sensitivity in oncology. Understanding the mechanistic basis and identification of robust biomarkers to predict collateral sensitivity may inform optimal use of chemotherapy in patients receiving multiple lines of treatment.

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Collateral sensitivity to novel thymidylate synthase inhibitors correlates with folate cycle enzymes impairment in cisplatin-resistant human ovarian cancer cells

Cited by 29 publications

References 40 publications

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

Transcriptional Activation and Cell Cycle Block Are the Keys for 5-Fluorouracil Induced Up-Regulation of Human Thymidylate Synthase Expression

Polo Like Kinase 2 Tumour Suppressor and cancer biomarker: new perspectives on drug sensitivity/resistance in cancer

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