Abstract
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.
Highlights
Breast cancer is a worldwide health concern with over two million new cases in 2020 [1]
The effect of MHI-palbociclib was compared to palbociclib and MHI-148 in breast cancer and non-cancerous cell lines, where cell proliferation, cell growth, and cell viability were examined (Figure 2)
The breast cancer estrogen receptor-positive MCF-7 cells showed a higher sensitivity than the triple-negative MDA-MB-231 cells towards palbociclib in the proliferation assay (Figure 2A), while the non-cancerous cells showed significantly increased resistance when compared to the breast cancer cell lines (Table 1 and Supplementary Materials Table S1)
Summary
Breast cancer is a worldwide health concern with over two million new cases in 2020 [1]. Significant advances have been made in understanding different breast cancers and several molecular subtypes of breast cancer have been characterized [2]. This knowledge has accelerated the development of new therapies to target molecular alterations that drive tumor cell growth. Abnormal proliferation with dysregulation of normal cell cycle control are common to all cancer types [3]. Cell cycle progression plays a crucial role in cell proliferation, and alterations in cell cycle regulators have been acknowledged as a hallmark of cancer [3]. Cyclin-dependent kinases, CDK4 and CDK6, drive cell cycle progression from the G0 or G1 phase into S phase, where DNA replication occurs [4]. CDK4/6 are appealing targets for novel cancer therapeutics [5]
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