Caspase-9: structure, mechanisms and clinical application

Radiotherapy is one of the major therapeutic strategies for cancer treatment. In the past decade, there has been growing interest in using high Z (atomic number) elements (materials) as radiosensitizers. New strategies in nanomedicine could help to improve cancer diagnosis and therapy at cellular and molecular levels. Metal-based nanoparticles usually exhibit chemical inertness in cellular and subcellular systems and may play a role in radiosensitization and synergistic cell-killing effects for radiation therapy. This review summarizes the efficacy of metal-based NanoEnhancers against cancers in both in vitro and in vivo systems for a range of ionizing radiations including gamma-rays, X-rays, and charged particles. The potential of translating preclinical studies on metal-based nanoparticles-enhanced radiation therapy into clinical practice is also discussed using examples of several metal-based NanoEnhancers (such as CYT-6091, AGuIX, and NBTXR3). Also, a few general examples of theranostic multimetallic nanocomposites are presented, and the related biological mechanisms are discussed.

Background: Gadolinium-based nanoparticles (GdNPs) have been used as theranostic sensitizers in clinical radiotherapy studies; however, the biomechanisms underlying the radiosensitizing effects of GdNPs have yet to be determined. In this study, ultra-small gadolinium oxide nanocrystals (GONs) were employed to investigate their radiosensitizing effects and biological mechanisms in non-small-cell lung cancer (NSCLC) cells under X-ray irradiation. Method and materials: GONs were synthesized using polyol method. Hydroxyl radical production, oxidative stress, and clonogenic survival after X-ray irradiation were used to evaluate the radiosensitizing effects of GONs. DNA double-strand breakage, cell cycle phase, and apoptosis and autophagy incidences were investigated in vitro to determine the radiosensitizing biomechanism of GONs under X-ray irradiation. Results: GONs induced hydroxyl radical production and oxidative stress in a dose- and concentration-dependent manner in NSCLC cells after X-ray irradiation. The sensitizer enhancement ratios of GONs ranged between 19.3% and 26.3% for the NSCLC cells under investigation with a 10% survival rate compared with that of the cells treated with irradiation alone. Addition of 3-methyladenine to the cell medium decreased the incidence rate of autophagy and increased cell survival, supporting the idea that the GONs promoted cytostatic autophagy in NSCLC cells under X-ray irradiation. Conclusion: This study examined the biological mechanisms underlying the radiosensitizing effects of GONs on NSCLC cells and presented the first evidence for the radiosensitizing effects of GONs via activation of cytostatic autophagy pathway following X-ray irradiation.

A novel organic–inorganic ratiometric fluorescent probe AuNCs–NBD was developed for the detection of cysteine (Cys) and homocysteine (Hcy). In our design, the AuNCs–NBD exhibited dual-emission fluorescence properties with a single excitation. Bovine serum albumin (BSA) protected gold nanoclusters (AuNCs) with carboxyl groups were employed as a reference signal unit and conjugated with the p-aminothiophenol substituted NBD (7-nitro-2,1,3-benzoxadiazole) moiety to form the ratiometric fluorescent probe. The AuNCs–NBD composite showed a single red fluorescence at 630 nm ascribed to AuNCs, and reaction of AuNCs–NBD with Cys and Hcy caused the cleavage of the thioether bond and therefore generated the fluorescent amino linked NBD with emission at 540 nm. Accordingly, the green fluorescence of released NBD at 540 nm gradually increased upon increasing the concentration of Cys or Hcy, while the red fluorescence ascribed to AuNCs at 630 nm remained constant, which resulted in the ratiometric determination of Cys and Hcy using the AuNCs–NBD probe. Due to the specific recognition of NBD with Cys and Hcy, the AuNCs–NBD probe exhibited high selectivity for Cys and Hcy over other amino acids and GSH. In addition, the AuNCs–NBD composite displayed desirable properties such as high specificity, appreciable solubility, ratiometric fluorescence response and favorable detection limit. Moreover, the AuNCs–NBD probe has been successfully applied for monitoring and imaging of intracellular Cys and Hcy in HeLa cells.

Heavy ion beams have advantages over conventional radiation in radiotherapy due to their superb biological effectiveness and dose conformity. However, little information is currently available concerning the cellular and molecular basis for heavy ion radiation-induced autophagy. In this study, human glioblastoma SHG44 and cervical cancer HeLa cells were irradiated with carbon ions of different linear energy transfers (LETs) and X-rays. Our results revealed increased LC3-II and decreased p62 levels in SHG44 and HeLa cells post-irradiation, indicating marked induction of autophagy. The autophagic level of tumor cells after irradiation increased in a LET-dependent manner and was inversely correlated with the sensitivity to radiations of various qualities. Furthermore, we demonstrated that high-LET carbon ions stimulated the unfolded protein response (UPR) and mediated autophagy via the UPR-eIF2α-CHOP-Akt signaling axis. High-LET carbon ions more severely inhibited Akt-mTOR through UPR to effectively induce autophagy. Thus, the present data could serve as an important radiobiological basis to further understand the molecular mechanisms by which high-LET radiation induces cell death.