Novel ruthenium(II) triazine complex [Ru(bdpta)(tpy)]²⁺ co-targeting drug resistant GRP78 and subcellular organelles in cancer stem cells

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>Ruthenium(II/III) metal complexes have been widely recognized as the alternative chemotherapeutic agents to overcome the drug resistance and tumor recurrence associated with platinum derivatives. In this work, a novel ruthenium(II) triazine complex namely, <B>1</B> ([Ru(bdpta)(tpy)]<SUP>2+</SUP>) was synthesized and spectroscopically characterized. Drug resistant cancer stem cells (CSCs) were used to evaluate the cytotoxicity of Ru(II) complex <B>1</B>. The complex <B>1</B> showed a greater cytotoxic potential with IC<SUB>50</SUB> values lower than that of cisplatin. The intracellular localization assay confirmed that the complex <B>1</B> was effectively distributed into mitochondria as well as endoplasmic reticulum (ER), and executed a ROS-mediated calcium and Bax/Bak dependent intrinsic apoptosis. Interestingly, direct interaction between complex <B>1</B> and glucose regulated protein 78 (GRP78), a protein associated with drug resistance caused the ROS-mediated ubiquitination of GRP78. Notably, western blot and confocal microscopy analysis confirmed that complex <B>1</B> significantly reduced the protein levels of GRP78. Dose-dependent <I>in vivo</I> antitumor efficacy against CD133+HCT-116 CSCs derived tumor xenograft further validated that complex <B>1</B> could be an effective chemotherapeutic agent.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The novel ruthenium(II) triazine complex <B>1</B> was synthesized and characterized. </LI> <LI> The cytotoxicity study of ruthenium(II) triazine complex <B>1</B> was evaluated against cisplatin in cancer stem cells (CSCs). </LI> <LI> Complex <B>1</B> was mainly accumulated in mitochondria and endoplasmic reticulum (ER). </LI> <LI> Direct interaction between complex <B>1</B> and glucose regulated protein 78 (GRP78), caused ROS mediated ubiquitination of GRP78. </LI> <LI> Dose-dependent <I>in vivo</I> antitumor efficacy of complex <B>1</B> was investigated. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>