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Hypoxia is a common feature of solid tumors and is considered to be the fatal flaw of conventional photodynamic therapy (PDT), which severely reduces the overall therapeutic efficacy. Here, we developed a series of halogenated photosensitizers to address this issue. The results showed that the introduction of heavy atoms enhanced the spin-coupling effect of the photosensitizers and effectively improved the type I PDT (non-oxygen-dependent) efficiency. The preferred iodine-substituted photosensitizer NRh–I was used as the basic architecture, and further nitrosyl modification was performed to obtain the NO small-molecule prodrug, which was finally encapsulated with DSPE-mPEG 5k to obtain a biocompatible NO nanophotocontrolled prodrug. By using the enhanced permeability and retention effect (EPR), the prodrug system can precisely target the lesion site, release a high concentration of NO by photocontrol, kill the tumor cells, and at the same time, cascade with ROS released with the same "time-space" precision to generate higher cytotoxicity, ONOO−, which generates a stronger targeted synergistic therapeutic effect. This "butterfly effect" strategy maximizes the effect of PDT and broadens the idea of translational medicine. [Display omitted] • Heavy atoms enhanced type I photosensitizer reactions. • Preferably NRh-I was modified into NO prodrug. • NO cascaded with ROS to form the more toxic ONOO-. • Liposome delivery increased drug delivery concentration. [ABSTRACT FROM AUTHOR]

This study was the first to investigate the synthesis of near-infrared light-sensitive NO prodrug [Mn(PaPy2Q)(NO)]ClO4, and detection the amount of NO released by the drug in different time and near infrared light (10 mW, 20 mW). It showed that with the increase of light power, the time required for the drug to release NO was shortened, and we selected 20 mW, 10 min as a follow-up study of light power and irradiation time while ensuring the near-infrared light did not affect tumor cells. The cells were irradiated with 20 mW of near-infrared light for 10 min at 6 h after treatment with the drug on PC-3, LNCaP and 22RV1 cells, and NO concentration and cell survival rate were tested at 12 h, 24 h and 48 h. Experiments showed that NO concentration remained stable within 48 h and [Mn(PaPy2Q)(NO)]ClO4 inhibited the proliferation of cells in a concentration and time-dependent manner. Then we also found that [Mn(PaPy2Q)(NO)]ClO4 increased the expression of apoptosis-related proteins (PARP, Bax, Caspase 3/9), inhibited the expression of BCl-2 and increased the activity level of Caspase 3/7, which showed [Mn(PaPy2Q)(NO)]ClO4 promoted prostate cancer cells apoptosis. Next, the results in xenograft mouse model showed that [Mn(PaPy2Q)(NO)]ClO4 also had anti-prostate cancer effects in vivo, and the NO concentration increased in the tumor after near-infrared light irradiation. After [Mn(PaPy2Q)(NO)]ClO4 treatment 6 weeks, tumor volume was significantly reduced, Ki67 and BrdU protein expression was significantly reduced. TUNEL assay results showed that [Mn(PaPy2Q)(NO)]ClO4 could promote the apoptosis of solid tumors in vivo and in a concentration-dependent manner.

The aim of this study was to investigate the effects of JS-K, a nitric oxide donor prodrug, on DNA damage and autophagy in bladder cancer (BCa) cells and to explore the potential related mechanisms. Through detecting proliferation viability, cell morphology observation and colony formation assay low concentrations of JS-K significantly inhibited BCa growth while having no effect on normal cells. JS-K induced an increase in the level of DNA damage protein γH2AX and a decrease in the level of DNA damage repair-related proteins PCNA and RAD51 in BCa cells, indicating that JS-K can induce DNA damage in BCa cells and inhibit DNA damage repair. JS-K induced G2/M phase block and calcium overload using flow cytometry analysis. Moreover, we also investigated the levels of cell G2/M cycle checkpoint-related protein and autophagy-associated protein by western blot. The results of our study demonstrated that JS-K induced BCa cells G2/M phase arrest due to upregulating proteins related to DNA damage-related G2/M checkpoint activation (p-ATM, p-ATR, p-Chk1, p-Chk2, and p-Cdc2) and down-regulation of Cyclin B1 protein. In addition, our study demonstrated that JS-K-induced autophagy in BCa cells was related to the CAMKKβ/AMPKα/mTOR pathway., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Previous studies have shown nitric oxide (NO) is involved in a variety of signal pathways in vivo, and plays an important role in lots of pathological and physiological processes, such as tumorigenesis and so on. The expression of glutathione S-transferase (GSTs) is upregulated in many tumors, which plays an important role in maintaining the balance of redox, detoxification, and resistence to chemotherapeutics for the tumor cells. In recent years, a novel NO prodrug named JS-K was synthesised, and JS-K can be selectively catalysed by GSTs, then NO is released, subsequently showing the anticancer effect. Many studies have demonstrated JS-K can inhibit the growth of a broad spectrum of tumors, while sparing the normal tissue cells. The mechanisms for JS-K to kill tumor cells are not always the same due to the differenrt origins of tumors in different systems. In this study, our team systemically reviewed the mechanisms for JS-K to kill tumors originating from different systems through extensive literature reading, with the purpose to providing some helpful ideas for the further study of JS-K and theoretical foundation for JS-K in the future clinical use. [ABSTRACT FROM AUTHOR]

This study was the first to investigate the synthesis of near-infrared light-sensitive NO prodrug [Mn(PaPy2Q)(NO)]ClO 4 , and detection the amount of NO released by the drug in different time and near infrared light (10 mW, 20 mW). It showed that with the increase of light power, the time required for the drug to release NO was shortened, and we selected 20 mW, 10 min as a follow-up study of light power and irradiation time while ensuring the near-infrared light did not affect tumor cells. The cells were irradiated with 20 mW of near-infrared light for 10 min at 6 h after treatment with the drug on PC-3, LNCaP and 22RV1 cells, and NO concentration and cell survival rate were tested at 12 h, 24 h and 48 h. Experiments showed that NO concentration remained stable within 48 h and [Mn(PaPy2Q)(NO)]ClO 4 inhibited the proliferation of cells in a concentration and time-dependent manner. Then we also found that [Mn(PaPy2Q)(NO)]ClO 4 increased the expression of apoptosis-related proteins (PARP, Bax, Caspase 3/9), inhibited the expression of BCl-2 and increased the activity level of Caspase 3/7, which showed [Mn(PaPy2Q)(NO)]ClO 4 promoted prostate cancer cells apoptosis. Next, the results in xenograft mouse model showed that [Mn(PaPy2Q)(NO)]ClO 4 also had anti-prostate cancer effects in vivo, and the NO concentration increased in the tumor after near-infrared light irradiation. After [Mn(PaPy2Q)(NO)]ClO 4 treatment 6 weeks, tumor volume was significantly reduced, Ki67 and BrdU protein expression was significantly reduced. TUNEL assay results showed that [Mn(PaPy2Q)(NO)]ClO 4 could promote the apoptosis of solid tumors in vivo and in a concentration-dependent manner. [Display omitted] • The NO prodrug inhibited the proliferation of PCa cells in a dose and time-dependent manner and induced apoptosis. • The NO prodrug could release high concentration NO by NIR in PCa cells. • The light-activated NO prodrug had anti-PCa effects in vivo. [ABSTRACT FROM AUTHOR]

Image 1., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)