5-O-(N-Boc-l-Alanine)-Renieramycin T Induces Cancer Stem Cell Apoptosis via Targeting Akt Signaling

Abstract

Cancer stem cells (CSCs) drive aggressiveness and metastasis by utilizing stem cell-related signals. In this study, 5-O-(N-Boc-l-alanine)-renieramycin T (OBA-RT) was demonstrated to suppress CSC signals and induce apoptosis. OBA-RT exerted cytotoxic effects with a half-maximal inhibitory concentration of approximately 7 µM and mediated apoptosis as detected by annexin V/propidium iodide using flow cytometry and nuclear staining assays. Mechanistically, OBA-RT exerted dual roles, activating p53-dependent apoptosis and concomitantly suppressing CSC signals. A p53-dependent pathway was indicated by the induction of p53 and the depletion of anti-apoptotic Myeloid leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins. Cleaved poly (ADP-ribose) polymerase (Cleaved-PARP) was detected in OBA-RT-treated cells. Interestingly, OBA-RT exerted strong CSC-suppressing activity, reducing the ability to form tumor spheroids. In addition, OBA-RT could induce apoptosis in CSC-rich populations and tumor spheroid collapse. CSC markers, including prominin-1 (CD133), Octamer-binding transcription factor 4 (Oct4), and Nanog Homeobox (Nanog), were notably decreased after OBA-RT treatment. Upstream CSCs regulating active Akt and c-Myc were significantly decreased; indicating that Akt may be a potential target of action. Computational molecular modeling revealed a high-affinity interaction between OBA-RT and an Akt molecule. This study has revealed a novel CSC inhibitory effect of OBA-RT via Akt inhibition, which may improve cancer therapy.

Novel Synthetic Derivative of Renieramycin T Right-Half Analog Induces Apoptosis and Inhibits Cancer Stem Cells via Targeting the Akt Signal in Lung Cancer Cells

“…Furthermore, a modified form of RT named 5- O -acetyl-renieramycin T eliminates lung CSCs and makes lung cancer cells more susceptible to cisplatin-mediated apoptosis [ 17 ]. 5- O -( N -Boc-l-alanine)-renieramycin T, another RT-modified compound, also binds and inhibits Akt function, resulting in apoptosis and cancer stem cell suppression [ 18 ]. A previous study of RT showed that this compound exerts apoptosis-induction effects by directly targeting Mcl-1, a key anti-apoptotic protein, and inducing its degradation through ubiquitin-proteasomal degradation [ 16 ].…”

“…GSK690693, an Akt inhibitor currently in phase I clinical trials, was reported to inhibit cancer cell proliferation and induce apoptosis in a subset of tumor cells with potency consistent with the intracellular inhibition of Akt kinase activity [ 45 ]. 5- O -(N-Boc-l-alanine)-renieramycin T and hydroquinone 5-O-cinnamoyl ester of renieramycin M, a series of renieramycin derivatives, showed CSC-suppression activities by inhibiting Akt signaling, resulting in the downregulation of CSC transcription factors (Nanog, Oct4, and Sox2) [ 18 , 32 ]. In this study, DH_25, a derivative of the RT right-half analog, efficiently inhibited and induced the death of lung CSCs ( Figure 4 A).…”

“…This may suggest that targeting Trp80 residues is the most critical factor in determining activity. By contrast, numerous allosteric Akt inhibitors exhibit more favorable interactions with specific Trp80 residues [ 18 , 51 ]. In addition, DH_25 showed a similar binding pattern to miransertib, an oral allosteric Akt-1 inhibitor, by VDW interaction with Trp80.…”

“…5- O -acetyl-renieramycin T was demonstrated to eliminate lung CSCs and make lung cancer cells more susceptible to cisplatin-mediated apoptosis [ 17 ]. Moreover, 5- O -( N -Boc-l-alanine)-renieramycin T (OBA-RT) showed a lung CSC-suppressing effect through Akt inhibition [ 18 ].…”

A novel MDM2-p53 antagonist APG115 exerts synergistic effect with ibrutinib via targeting MCL-1 in chronic lymphocytic leukemia

“…Similarly, APG115 can synergistically promote apoptosis of ibrutinib by promoting MCL-1 degradation 45,47,48 . The current potential application direction of APG115 is cooperating with cancer immunotherapy.…”