Abstract
In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca2+)–calmodulin (CaM) complex and induce an overload of intracellular Ca2+, resulting in the induction of non-apoptotic programmed cell death. In this work, we conduct a detailed mechanistic study of cell death induced by ASb-2, a typical example of IPHs, and describe how ASb-2 induces paraptotic programmed cell death in a manner similar to that of celastrol, a naturally occurring triterpenoid that is known to function as a paraptosis inducer in cancer cells. It is suggested that ASb-2 (50 µM) induces ER stress and decreases the mitochondrial membrane potential (ΔΨm), thus triggering intracellular signaling pathways and resulting in cytoplasmic vacuolization in Jurkat cells (which is a typical phenomenon of paraptosis), while the change in ΔΨm values is negligibly induced by celastrol and curcumin. Other experimental data imply that both ASb-2 and celastrol induce paraptotic cell death in Jurkat cells, but this induction occurs via different signaling pathways.
Highlights
Programmed cell death (PCD) is an important pathway controlled by intracellular organelles and is referred as cellular suicide
We reported on the design and synthesis of cyclometalated iridium(III) (Ir(III)) complex–peptide hybrids (IPHs) that contain cationic peptides such as a KK(K)GG (K: lysine, G: glycine) sequence that are attached via alkyl chain linkers and which exhibit considerable cytotoxicity against Jurkat cells by the induction of cellular morphological changes [40,41,42,43,44,45]
The relationship of autophagy with cell death induced by ASb-2 is discussed, as we reported on the upregulation of some marker proteins of autophagy in Jurkat cells treated with other Ir complex–peptide hybrids (IPHs) in our previous publications [42,44]
Summary
Programmed cell death (PCD) is an important pathway controlled by intracellular organelles and is referred as cellular suicide. Numerous antitumor drugs have been developed that induce the apoptosis of cancer, their action is not sufficient for the elimination of cancer cells through typical forms of caspase-dependent PCD. The induction of non-apoptotic types of PCD such as necroptosis, autophagy, and pyroptosis represents new effective approaches for fighting cancer cells [4,5]. Autophagic cell death has been identified as non-caspase-dependent type of PCD accompanied by plasma membrane blebbing, autophagic vacuoles in the cytoplasm, enlarged organelles, large intracellular vesicles, and the absence of chromatin condensation [6]. Paraptosis has recently been recognized as another non-caspase-dependent type of PCD, as evidenced by the development of endoplasmic reticulum (ER) stress, extensive cytoplasmic vacuolization, and swelling or the dysfunction of the ER and/or mitochondria [7,8,9,10,11]. The mechanism responsible for the paraptosis in cancer cells that is induced by these molecules appears to be complicated and has not yet been extensively studied
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
