Your browser doesn't support javascript.
loading
Overcoming Resistance in Prostate Cancer Therapy Using a DZ-Simvastatin Conjugate.
Ou, Yan; Chu, Gina Chia-Yi; Lyu, Ji; Yin, Liyuan; Lim, Adrian; Zhai, Ning; Cui, Xiaojiang; Lewis, Michael S; Edderkaoui, Mouad; Pandol, Stephen J; Wang, Ruoxiang; Zhang, Yi.
Afiliação
  • Ou Y; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Chu GC; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Lyu J; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Yin L; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Lim A; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Zhai N; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Cui X; Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, California 90048, United States.
  • Lewis MS; Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Edderkaoui M; Department of Pathology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Pandol SJ; VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, California 90073, United States.
  • Wang R; Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
  • Zhang Y; Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, United States.
Mol Pharm ; 21(2): 873-882, 2024 Feb 05.
Article em En | MEDLINE | ID: mdl-38229228
ABSTRACT
Prostate cancer (PC), particularly its metastatic castration-resistant form (mCRPC), is a leading cause of cancer-related deaths among men in the Western world. Traditional systemic treatments, including hormonal therapy and chemotherapy, offer limited effectiveness due to tumors' inherent resistance to these therapies. Moreover, they often come with significant side effects. We have developed a delivery method using a tumor-cell-specific heptamethine carbocyanine dye (DZ) designed to transport therapeutic agents directly to tumor cells. This research evaluated simvastatin (SIM) as the antitumor payload because of its demonstrated chemopreventive effects on human cancers and its well-documented safety profile. We designed and synthesized a DZ-SIM conjugate for tumor cell targeting. PC cell lines and xenograft tumor models were used to assess tumor-cell targeting specificity and killing activity and to investigate the corresponding mechanisms. DZ-SIM treatment effectively killed PC cells regardless of their androgen receptor status or inherent therapeutic resistance. The conjugate targeted and suppressed xenograft tumor formation without harming normal cells of the host. In cancer cells, DZ-SIM was enriched in subcellular organelles, including mitochondria, where the conjugate formed adducts with multiple proteins and caused the loss of transmembrane potential, promoting cell death. The DZ-SIM specifically targets PC cells and their mitochondria, resulting in a loss of mitochondrial function and cell death. With a unique subcellular targeting strategy, the conjugate holds the potential to outperform existing chemotherapeutic drugs. It presents a novel strategy to circumvent therapeutic resistance, offering a more potent treatment for mCRPC.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinvastatina / Neoplasias de Próstata Resistentes à Castração Limite: Humans / Male Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinvastatina / Neoplasias de Próstata Resistentes à Castração Limite: Humans / Male Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos