A concise, one-step route to produce 3,3′-diindolylmethanes (DIMs) from simple indoles and ketones or aldehydes is reported. The key step is the ready formation of indole derivatives that involves the in situ conversion of CF 3 SO 2 Na reagent to •CF 3 under oxygen or air (1.0 atm) and UV irradiation. It is disclosed that most of the obtained DIMs show anticancer activities in human bladder cancer cell lines EJ and T24.

Vitamin K2 has been shown to exert remarkable anticancer activity. However, the detailed mechanism remains unclear. Here, our study was the first to show that Vitamin K2 significantly promoted the glycolysis in bladder cancer cells by upregulating glucose consumption and lactate production, whereas inhibited TCA cycle by reducing the amounts of Acetyl-CoA. Moreover, suppression of PI3K/ AKT and HIF-1α attenuated Vitamin K2-increased glucose consumption and lactate generation, indicating that Vitamin K2 promotes PI3K/AKT and HIF-1α-mediated glycolysis in bladder cancer cells. Importantly, upon glucose limitation, Vitamin K2-upregulated glycolysis markedly induced metabolic stress, along with AMPK activation and mTORC1 pathway suppression, which subsequently triggered AMPK-dependent autophagic cell death. Intriguingly, glucose supplementation profoundly abrogated AMPK activation and rescued bladder cancer cells from Vitamin K2-triggered autophagic cell death. Furthermore, both inhibition of PI3K/AKT/HIF-1α and attenuation of glycolysis significantly blocked Vitamin K2-induced AMPK activation and subsequently prevented autophagic cell death. Collectively, these findings reveal that Vitamin K2 could induce metabolic stress and trigger AMPK-dependent autophagic cell death in bladder cancer cells by PI3K/AKT/HIF-1α-mediated glycolysis promotion. Cancer cells, including bladder carcinoma cells, display the altered metabolism, compared to normal cells 1. One of the most metabolic shifts in cancer cells is the aberrant glucose metabolism. Unlike the normal cells, most cancer cells exhibit the remarkably increased glucose uptake and glycolysis rate to meet their rapid proliferation and metastasis 2. Moreover, numerous studies indicate that the glycolysis is usually uncoupled from the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Therefore, pyruvate, the end product of glycolysis, is mainly diverted to lactate production, with the reduction of mitochondrial TCA cycle and OXPHOS 3. This metabolic shift is well-known as the Warburg effect. However, in tumor microenvironment, the nutrients including glucose are limited. Excessively increasing glycolysis will inevitably result in intracellular metabolic stress and trigger cancer cell death due to energy depletion 4. Therefore, in nutrient-deficient tumor microenvironment, the method of promoting glycolysis to induce metabolic stress and activate cell death appears to be a novel strategy for cancer treatment. Phosphatidylinositide-3-kinase (PI3K) and AKT are usually hyper-activated in cancer cells. There are accumulating evidences indicating that activation of PI3K and AKT plays a pivotal role in the regulation of aerobic glycolysis in cancer cells 5-7. The activated PI3K/AKT can directly promote the shift to the aerobic glycolysis, rendering cancer cells more reliance on glucose consumption for lactate generation 8,9. Although activation of PI3K and AKT could directly stimulate the aerobic glycolysis by positive regulation of some glycol...

A convenient photocatalyst‐free method for the synthesis of redox‐active 1,2‐dihydro‐3H‐indazol‐3‐one derivatives from (2‐nitroaryl)methanol and amines was developed. The reaction proceeded efficiently at room temperature by irradiation of UV light under CO2 atmosphere (1.0 atm, flow) without any photocatalysts or additives. This mild, operationally simple method shows wide functional tolerance. The carbamate formed in situ from CO2 and amine is proposed to be the key of this reaction. Some of these compounds synthesized by the present method were found to exhibit high anticancer activities, which can lower the viability of cancerous cell lines such as HeLa, MCF‐7 and U87.

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a key role in biosynthesis of vitamin K2 and coenzyme Q10 using geranylgeranyl diphosphate (GGPP). However, the mechanism by which UBIAD1 participates in tumorigenesis remains unknown. This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. In addition, GGPP was required to maintain the function of UBIAD1 in regulating the Ras/ERK signaling pathway. A Drosophila model was employed to confirm the function of UBIAD1/HEIX in vivo. The activation of Ras/ERK signaling at the plasma membrane induced melanotic masses in Drosophila larvae. Our study suggests that UBIAD1 serves as a tumor suppressor in cancer and tentatively reveals the underlying mechanism of melanotic mass formation in Drosophila.

PPM-18, identified as a novel analog of vitamin K, has been reported to play a critical role in the suppression of seizures. However, the concerns that whether PPM-18, like vitamin K, exerts anticancer activity remain to be further investigated. Here, we found that PPM-18 remarkably suppressed the proliferation and induced apoptosis in bladder cancer cells. Furthermore, a significant autophagic effect of PPM-18 on bladder cancer cells was also demonstrated, which profoundly promoted apoptotic cell death. Mechanistically, PPM-18 activated AMP-activated protein kinase (AMPK), whereas it repressed PI3K/AKT and mTORC1 pathways in bladder cancer cells. Inhibition of AMPK markedly relieved PPM-18–induced autophagy and apoptosis, indicating that PPM-18 is able to induce autophagy and apoptosis in bladder cancer cells via AMPK activation. Moreover, reactive oxygen species (ROS) were notably accumulated in PPM-18–treated bladder cancer cells, and treatment with ROS scavengers not only eliminated ROS production but also abrogated AMPK activation, which eventually rescued bladder cancer cells from PPM-18–triggered autophagy and apoptotic cell death. In bladder cancer xenografts, the anticancer activities of PPM-18, including suppressing the growth of tumors and inducing autophagy and apoptosis in tumor cells, were also established. Collectively, this study was the first to demonstrate the anticancer effect of PPM-18 on bladder cancer cells in vitro and in vivo through eliciting autophagy and apoptosis via ROS and AMPK pathways, which might provide new insights into the potential utilization of PPM-18 for future bladder cancer treatment.