Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action
Peter Jaein Choi,
Petr Tomek,
Moana Tercel,
Jóhannes Reynisson,
Thomas In Hyeup Park,
Elizabeth Alexandra Cooper,
William Alexander Denny,
Jiney Jose,
Euphemia Leung
Affiliations
Peter Jaein Choi
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
Petr Tomek
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
Moana Tercel
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
Jóhannes Reynisson
School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle under Lyme, Staffordshire ST5 5BG, UK
Thomas In Hyeup Park
Neurosurgical Research Unit & Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand
Elizabeth Alexandra Cooper
Neurosurgical Research Unit & Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1023, New Zealand
William Alexander Denny
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
Jiney Jose
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
Euphemia Leung
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
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.
