Abstract 4467: Differential response of ERa-targeted therapy in breast and ovarian cancer cells by 17b-estradiol-linked platinum(II) hybrid (E2-Pt(II)), VP-128
Bibliographic record
Abstract
Abstract Biological targets, like ERα in hormone-dependant cancer therapies, are the focus of many cancer research groups. We have previously reported the synthesis of a new 17β-estradiol-linked platinum(II) hybrid (E2-Pt(II)), VP-128, that binds to ERα with high affinity. This drug has also demonstrated high biological activity towards breast (MCF-7, ZR-75-1, MDA-MB-468, MDA-MB-231 and HS578-T) and ovarian (OVCAR-3, SKOV-3, A2780, and A2780-CP) cancer cells, in vitro and in vivo using ERα positive or negative cells. MTT assays revealed that VP-128 decreased more efficiently the viability of breast and ovarian cancer cells than cisplatin itself in vitro. Moreover, the expression of ERα sensitized the cells to the growth-suppressive effect of VP-128. Hoechst nuclear staining revealed an improved efficiency of VP-128 compared to cisplatin to induce apoptosis of breast cancer cells, which was enhanced in ERα-positive cells. Western blot analysis revealed that VP-128 induced more caspase-9 fragments, but less caspase-3 and PARP fragments in breast cancer cells compared to cisplatin, suggesting that the two drugs have a different mode of action. Nonetheless, VP-128 and cisplatin similarly decreased the levels of XIAP and phosphorylated/active Akt in sensitive cells. RT-PCR analysis showed that ERα is expressed and activated in response to E2 and VP-128 in MCF-7 cells, as indicated by an increase of pS2 and c-myc transcripts. Although exposure to E2 induced TGF-β3 expression in both ERα+/ERβ+ MCF-7 cells and ERα-/ERβ+ MDA-MB-468 cells, VP-128 induced TGF-β3 expression only in MCF-7 cells. This suggests that VP-128 induces TGF-β3 expression in an ERα-dependent mechanism. In agreement, western blot analysis showed that at each dose tested, VP-128 treatment rapidly induced the translocation of ERα to the nucleus in MCF-7 cells, similar to E2 treatment, whereas ERβ was imported to the nucleus in response to E2 but not to VP-128. The activation of caspase-independent apoptosis was observed in MDA-MB-468 cells, where VP-128 rapidly induced the translocation of AIF to the nucleus, as revealed by western blot analysis of cytosolic and nuclear cell extracts. AIF subcellular localization was not modified by VP-128 in MCF-7 cells. Finally, using human breast and ovarian cancer cell xenografts in nude mice, we found that VP-128 had improved antitumour activity compared to cisplatin in vivo, and was more specific and selective towards hormone-dependent cancer cells. Altogether these results highlight the therapeutic value of this unique E2-Pt(II) hybrid for the treatment of hormone-dependent breast cancers, and provide preliminary proof-of-concept for efficient targeting of ERα by E2-cisplatin hybrids. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4467.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".