RESUMEN
Melanoma is the most threatening form of metastatic skin cancer that develops from melanocytes and causes a large majority of deaths due to poor therapeutic prognosis. It has significant limitations in treatment because it shows great resistance to chemotherapy, radiotherapy, and other therapeutic methods. A noninvasive and clinically accepted therapeutic modality, photodynamic therapy (PDT), is a promising treatment option, but it is limitedly applied for melanoma skin cancer treatment. This is because most of the photosensitizers are unlikely to be expected to have a remarkable effect on melanoma due to drug efflux by melanin pigmentation and intrinsic antioxidant defense mechanisms. Moreover, melanin is a dominant absorber in the spectral region of 500-600 nm that can cause the decreased photoreaction efficiency of photosensitizers. Herein, to overcome these drawbacks, we have developed a phenylthiourea-conjugated BODIPY photosensitizer (PTUBDP) for tyrosinase-positive melanoma-targeted PDT. In light of our results, it exhibited an enhanced cytotoxic efficacy compared to BDP, a parallel PDT agent that absence of phenylthiourea unit. PTUBDP shows outstanding effects of increased oxidative stress by an enhanced cellular uptake of the tyrosinase positive melanoma cell line (B16F10). This work presents increased therapeutic efficacy through the combined therapeutic approach, enabling enhanced reactive oxygen species (ROS) generation as well as overcoming the critical limitations of melanoma.
Asunto(s)
Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Melanoma/tratamiento farmacológico , Monofenol Monooxigenasa/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Compuestos de Boro/química , Compuestos de Boro/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ensayo de Materiales , Melanoma/metabolismo , Melanoma/patología , Estructura Molecular , Tamaño de la Partícula , Feniltiourea/química , Feniltiourea/farmacología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
Cancer stem cells (CSCs), also called tumor-initiating cells (TICs), have been studied intensively due to their rapid proliferation, migration, and role in the recurrence of cancer. In general, CSC marker-positive cells [CD133, CD44, CD166, aldehyde dehydrogenase (ALDH), and epithelial cell adhesion molecule (EpCAM)] exhibit a 100-fold increased capacity to initiate cancer. Within a heterogeneous tumor mass, only approximately 0.05-3% of cells are suspected to be CSCs and able to proliferate under hypoxia. Interestingly, CSCs, cancer cells, and normal stem cells share many cytochemical properties, such as inhibition of the redox system for reactive oxygen species (ROS) production and high expression of drug resistance transporters. However, compared to normal stem cells, CSCs develop unique metabolic flexibility, which involves switching between oxidative phosphorylation (OXPHOS) and glycolysis as their main source of energy. Due to the similarities between CSCs and other cancer cells and normal stem cells, limited chemotherapeutic and bio-imaging reagents specific for CSCs have been developed. In this short review, we address the current knowledge regarding CSCs with a focus on designing chemotherapeutic and bio-imaging reagents that target CSCs.
Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/análisis , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Humanos , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patologíaRESUMEN
Human NAD(P)H:quinone oxidoreductase 1 (hNQO1) is overexpressed in cancer cells and associated with the drug resistance factor of cancer. The objective of this work is the development of fluorescent probes for the efficient detection of hNQO1 activity in cancer cells, which can be employed for the cancer diagnosis and therapeutic agent development. Herein, we report naphthalimide-based fluorescent probes 1 and 2 that can detect hNQO1. For hNQO1 activity, the probes showed a significant fluorescence increase at 540 nm. In addition, probe 1, the naphthalimide containing a triphenylphosphonium salt, showed an enhanced enzyme efficiency and rapid detection under a physiological condition. The detection ability of probe 1 was superior to that of other previously reported probes. Moreover, probe 1 was less cytotoxic during the cancer cell imaging and readily provided a strong fluorescence in hNQO1-overexpressed cancer cells (A549). We proposed that probe 1 can be used to detect hNQO1 expression in live cells and it will be applied to develop the diagnosis and customized treatment of hNQO1-related disease.