Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action
The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast can...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/3/880 |
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| author | Peter Jaein Choi Petr Tomek Moana Tercel Jóhannes Reynisson Thomas In Hyeup Park Elizabeth Alexandra Cooper William Alexander Denny Jiney Jose Euphemia Leung |
| author_facet | Peter Jaein Choi Petr Tomek Moana Tercel Jóhannes Reynisson Thomas In Hyeup Park Elizabeth Alexandra Cooper William Alexander Denny Jiney Jose Euphemia Leung |
| author_sort | Peter Jaein Choi |
| collection | DOAJ |
| description | The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case. |
| first_indexed | 2024-03-09T23:28:45Z |
| format | Article |
| id | doaj.art-e671aec5e09f4bc3b420e8a46419a8b3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T23:28:45Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e671aec5e09f4bc3b420e8a46419a8b32023-11-23T17:13:59ZengMDPI AGMolecules1420-30492022-01-0127388010.3390/molecules27030880Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of ActionPeter Jaein Choi0Petr Tomek1Moana Tercel2Jóhannes Reynisson3Thomas In Hyeup Park4Elizabeth Alexandra Cooper5William Alexander Denny6Jiney Jose7Euphemia Leung8Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New ZealandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New ZealandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New ZealandSchool of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle under Lyme, Staffordshire ST5 5BG, UKNeurosurgical Research Unit & Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1023, New ZealandNeurosurgical Research Unit & Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1023, New ZealandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New ZealandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New ZealandAuckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New ZealandThe CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.https://www.mdpi.com/1420-3049/27/3/880CDK4/6 inhibitor palbociclibnear-infrared fluorescent (NIRF)MHI-148breast cancercell cycle arrest |
| spellingShingle | Peter Jaein Choi Petr Tomek Moana Tercel Jóhannes Reynisson Thomas In Hyeup Park Elizabeth Alexandra Cooper William Alexander Denny Jiney Jose Euphemia Leung Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action Molecules CDK4/6 inhibitor palbociclib near-infrared fluorescent (NIRF) MHI-148 breast cancer cell cycle arrest |
| title | Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action |
| title_full | Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action |
| title_fullStr | Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action |
| title_full_unstemmed | Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action |
| title_short | Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action |
| title_sort | conjugation of palbociclib with mhi 148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action |
| topic | CDK4/6 inhibitor palbociclib near-infrared fluorescent (NIRF) MHI-148 breast cancer cell cycle arrest |
| url | https://www.mdpi.com/1420-3049/27/3/880 |
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