Vitamin E-Conjugated Phosphopeptide Inhibitor of the Polo-Box Domain of Polo-Like Kinase 1.
Min Su YimNak Kyun SoungEun Hee HanJin-Young MinHoJin HanEun-Ju SonHak Nam KimBoYeon KimJeong Kyu BangEun Kyoung RyuPublished in: Molecular pharmaceutics (2019)
Polo-like kinase 1 (Plk1) regulates cell cycle and cell proliferation, and is currently considered a potential biomarker in clinical trials for many cancers. A characteristic feature of Plks is their C-terminal polo-box domain (PBD). Pro-Leu-His-Ser-pThr (PLHS[pT])-the phosphopeptide inhibitor of the PBD of Plk1-induces apoptosis in cancer cells. However, because of the low cell membrane-penetration ability of PLHS[pT], new approaches are required to overcome these drawbacks. We therefore developed a vitamin E (VE) conjugate that is biodegradable by intracellular redox enzymes as an anticancer drug-delivery system. To ensure high efficiency of membrane penetration, we synthesized VE-S-S-PLHS[pT]KY (1) by conjugating PLHS[pT] to VE via a disulfide bond. We found that 1 penetrated cancer cell membranes, blocked cancer cell proliferation, and induced apoptosis in cancer cells through cell cycle arrest in the G2/M phase. We synthesized a radiolabeled peptide (124I-1), and the radioligand was evaluated in in vivo tumor uptake using positron emission tomography. This study shows that combination conjugates are an excellent strategy for specifically targeting Plk PBD. These conjugates have a dual function, with possible uses in anticancer therapy and tumor diagnosis.
Keyphrases
- cell cycle
- cell proliferation
- positron emission tomography
- induced apoptosis
- pi k akt
- cell cycle arrest
- high efficiency
- cancer therapy
- computed tomography
- clinical trial
- endoplasmic reticulum stress
- drug delivery
- signaling pathway
- cell death
- transcription factor
- papillary thyroid
- binding protein
- protein kinase
- pet ct
- pet imaging
- stem cells
- squamous cell
- photodynamic therapy
- deep learning
- childhood cancer
- young adults
- randomized controlled trial
- anti inflammatory
- open label
- replacement therapy
- smoking cessation