Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells

Authors

  • Slavomir Krajnak Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany. Telephone: +49 (0) 6131-17-0; E-mail: slavomir.krajnak@unimedizin-mainz.de https://orcid.org/0000-0002-8012-5772
  • Jannis Patrik Trier Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0003-2068-7623
  • Pauline Friederike Heinzmann Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0001-8596-3639
  • Katharina Anic Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0002-3001-5452
  • Anne-Sophie Heimes Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0001-5472-5224
  • Amelie Loewe Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0003-3384-371X
  • Marcus Schmidt Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0003-1365-2414
  • Marco Johannes Battista Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0003-2363-5001
  • Annette Hasenburg Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0002-1547-4968
  • Walburgis Brenner Clinic for Obstetrics and Women’s Health, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany https://orcid.org/0000-0002-1511-6212

DOI:

https://doi.org/10.17179/excli2022-5064

Keywords:

low-dose metronomic chemotherapy, PIK3CA mutation, vinorelbine, alpelisib, breast cancer

Abstract

In metastatic breast cancer (MBC), PIK3CA mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type PIK3CA) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by PIK3CA gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of PIK3CA-mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, PIK3CA wild-type BC cells. The p110α expression was downregulated or not affected in PIK3CA-mutated cell lines, and not significantly upregulated in PIK3CA wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, PIK3CA-mutated BC cells, providing a rationale for further efforts to evaluate this combination in vivo.

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Published

2023-01-13

How to Cite

Krajnak, S., Trier, J. P., Heinzmann, P. F., Anic, K., Heimes, A.-S., Loewe, A., … Brenner, W. (2023). Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells. EXCLI Journal, 22, 114–130. https://doi.org/10.17179/excli2022-5064

Issue

Vol. 22 (2023)

Section

Original articles

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Copyright (c) 2023 Slavomir Krajnak, Jannis Patrik Trier, Pauline Friederike Heinzmann, Katharina Anic, Anne-Sophie Heimes, Amelie Loewe, Marcus Schmidt, Marco Johannes Battista, Annette Hasenburg, Walburgis Brenner

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