Programmed Cell Death in Cancer Cells: Overcoming Resistance Through Paraptosis-inducing Compounds
Researchers from Japan have developed novel complex-peptide hybrids, which can induce programmed cell death in apoptosis-resistant cancer cells
Inducing programmed cell death (PCD), such as apoptosis, is a widely used therapeutic option for the treatment of cancer. Unfortunately, many cancer cells become resistant to PCDs, and continue multiplying. In a new study, researchers from Tokyo University of Science synthesized new complex-hybrid compounds named triptycene-peptide hybrids (TPHs), which successfully induced a kind of PCD known as paraptosis in Jurkat cells―a type of lymphocytes. These paraptosis-inducing compounds can revolutionize cancer therapy in the future.
Apoptosis, a type of programmed cell death (PCD), is a biological process through which unwanted cells are eliminated in multicellular organisms. In most cells, certain proteins known as "caspases" trigger apoptosis. This process is especially important for the treatment of cancer, since inducing cell death in cancer cells can help in their elimination.
Other than apoptosis, several types of PCDs occur in cells, including paraptosis, necroptosis, and autophagy. Of these, paraptosis is the most recently identified type of PCD, which is caused by the influx of excess calcium in the cells, leading to cell death.
Cancer cells often become resistant to drugs that induce apoptosis and other types of PCDs. In such cases, inducing paraptosis, which is not dependent on caspases, could act as a promising anti-cancer treatment. Hence, the development of compounds that can induce paraptosis in cancer cells is crucial.
To this end, a team of researchers from the Tokyo University of Science, led by Prof. Shin Aoki in collaboration with Mr. Kohei Yamaguchi and Dr. Kenta Yokoi, conducted a study to develop novel complex-peptide hybrids with paraptosis-inducing potential. This study was made available online on 11 April 2022, and subsequently published in Volume 33 of the journal Bioconjugate Chemistry, on 20 April 2022.
"Previously, we synthesized an iridium complex-peptide hybrid compound and observed that it induced cell death in cancer cells, which was different from apoptosis. Since this compound was unlike other paraptosis-inducing compounds, we wanted to understand its mechanism of paraptosis induction. Our goal now is to synthesize new compounds and elucidate how they induce paraptosis in cells, before we share this crucial information with the public," explains Prof. Aoki while discussing the team's motivation behind this study.
The newly synthesized compounds were composed of a triptycene core―an aromatic hydrocarbon―with two or three cationic peptides made of the amino acids lysine and glycine (represented as KKKGG) through a C8 alkyl linker chain, at different positions of the triptycene units. As a result, three triptycene core hybrids (TPHs) were produced, namely, 5, syn-6, and anti-6.
The team subsequently performed experiments on Jurkat cells, a type of immortalized human lymphocytes used in research, to understand the type of PCD that occurred in these cells on treatment with syn-6 and anti-6. They found that death in these cells was inhibited by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) which is an uncoupling reagent and an inhibitor of mitochondrial calcium uptake, RuRed, which is an inhibitor of the mitochondrial calcium channel), and 2-aminoethoxydiphenyl borate (2-APB), which is an inhibitor of D-inositol-1,4,5-trisphosphate receptor. However, cell death was not inhibited by inhibitors of the other types of PCDs.
Hence, they ruled out autophagy, necroptosis, and apoptosis, confirming that paraptosis is a major PCD pathway induced by syn-6 and anti-6 in Jurkat cells.
"Studies have indicated that the TPHs syn-6 and anti-6 induce the transfer of excess calcium from the endoplasmic reticulum (ER) to mitochondria, resulting in a loss of mitochondrial membrane potential. It is very likely that these phenomena are strongly related with the fusion of the ER with the mitochondria, followed by cytoplasmic vacuolization, resulting in cell death," said Prof. Aoki, when asked why these two TPHs were selected for the study. The TPHs syn-6, and anti-6 are more hydrophilic than other TPHs, which could also be a reason for their high paraptosis-inducing anti-cancer potential.
Through additional imaging experiments, the team detected the presence of cytoplasmic vacuolization, elevated mitochondrial calcium concentrations, and the degradation of the ER in Jurkat cells treated with syn-6 and anti-6.
Based on previous findings, the team hypothesized that in Jurkat cells as well, the influx of calcium in the mitochondria might be facilitated by the close proximity of the ER and the mitochondria. As expected, they found that the ER and mitochondrial membranes were attached to one another, facilitating direct transfer of calcium.
These findings confirmed that Jurkat cells treated with syn-6 and anti-6 had undergone programmed cell death, owing to paraptosis. They also provide crucial information for the design of compounds that can be used as therapeutic agents against cancer and other diseases.
Here's hoping that these promising findings contribute to the development of effective therapy against the ever-evolving cancer cells.
|Title of original paper||:||Design, Synthesis, and Anticancer Activity of Triptycene-Peptide Hybrids that Induce Paraptotic Cell Death in Cancer Cells|
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of "Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
About Professor Shin Aoki from Tokyo University of Science
Professor Shin Aoki is a professor of cancer biology & research at the Faculty of Pharmaceutical Sciences, Tokyo University of Science. He is engaged in the study of medicinal chemistry, pharmacology, bioinorganic chemistry, and supramolecular chemistry. He is a recipient of the Award of Japan Society of Coordination Chemistry for Young Scientists (1999); the AJINOMOTO Award in Synthetic Organic Chemistry, Japan (2001); and the Pharmaceutical Society of Japan Award for Young Scientists (2002). He is a graduate from the University of Tokyo with B. S. (1986), M.S. (1988), and Ph.D. (1992) degrees in pharmaceutical sciences. He holds a post doctorate degree from the Department of Chemistry, the Scripps Research Institute, USA.
This study was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, a research grant from the Uehara Memorial Foundation, a research grant from the Tokyo Ohka Foundation for the Promotion of Science and Technology, Kanagawa, Japan, and a research grant from the Tokyo Biochemical Research Foundation, Tokyo, Japan.