posted on 2024-01-17, 05:04authored byYan Ou, Gina Chia-Yi Chu, Ji Lyu, Liyuan Yin, Adrian Lim, Ning Zhai, Xiaojiang Cui, Michael S. Lewis, Mouad Edderkaoui, Stephen J. Pandol, Ruoxiang Wang, Yi Zhang
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.