No abstract

Background: Cancer is a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that inhibit oncogenic signaling pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development of many cancers. Several mTOR inhibitors are approved for the treatment of cancers. However, the anticancer efficacies of mTOR inhibitor monotherapy are still limited. Methods: Western blot was used to detect the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in cells was determined by the endpoint insulin reduction assay. Immunofluorescence staining was used to analyze precise location and expression of target proteins. Nude mice were used for xenograft tumor models. Results: We identified a synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the underlying molecular mechanisms of this synergism. We demonstrated that mTOR and TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found that auranofin (AF) combined with everolimus significantly suppressed tumor growth in HCT116 and SGC-7901 xenograft models with no significant signs of toxicity. Conclusion: Our findings identify a promising therapeutic combination for cancer and has important implications for developing mTOR inhibitor-based combination treatments.

Colon cancer is one of the leading causes of cancer-related death in the world. The development of new drugs and therapeutic strategies for patients with colon cancer are urgently needed. Isodeoxyelephantopin (ESI), a sesquiterpene lactone isolated from the medicinal plant Elephantopus scaber L., has been reported to exert antitumor effects on several cancer cells. However, the molecular mechanisms underlying the action of ESI is still elusive. In the present study, we found that ESI potently suppressed cell proliferation in human colon cancer cells. Furthermore, our results showed that ESI treatment markedly increased cellular reactive oxygen species (ROS) levels by inhibiting thioredoxin reductase 1 (TrxR1) activity, which leads to activation of the JNK signaling pathway and eventually cell death in HCT116 and RKO cells. Importantly, we found that ESI markedly enhanced cisplatin-induced cytotoxicity in HCT116 and RKO cells. Combination of ESI and cisplatin significantly increased the production of ROS, resulting in activation of the JNK signaling pathway in HCT116 and RKO cells. In vivo, we found that ESI combined with cisplatin significantly suppressed tumor growth in HCT116 xenograft models. Together, our study provide a preclinical proof-of-concept for ESI as a potential strategy for colon cancer treatment.

A b s t r a c tIntroduction: Childhood-onset schizophrenia with obsessive-compulsive symptoms (COSO) and without obsessive-compulsive symptoms (COS) share considerable overlap in clinical features and genetic risk factors. However, the extent of brain functional abnormalities in COSO and COS is poorly understood. Material and methods: A total of 51 first-episode childhood schizophrenic patients and 30 healthy age-and sex-matched controls were recruited. We used the Yale-Brown Obsessive Compulsive Scale to divide patients into COSO (n = 21) and COS (n = 30) groups. Resting-state functional magnetic resonance imaging images were obtained using a gradient-echo echo-planar imaging sequence. Voxel-based analysis of amplitude of low-frequency fluctuation (ALFF) maps between the two groups was performed. Results: The COS group showed significantly increased ALFF in the right caudate body, middle temporal gyrus and inferior parietal lobule (p < 0.05), while showing decreased ALFF in the left cerebellum posterior lobe (p < 0.05). The COSO group showed significantly increased ALFF in the left and right frontal lobe, cerebellum posterior lobe and precuneus (p < 0.05). When comparing the two groups, COSO showed significantly higher ALFF in the left cerebellum posterior lobe, frontal lobe, supramarginal gyrus, precuneus, right inferior frontal gyrus and medial frontal gyrus (p < 0.05). Interestingly, significantly lower ALFF was found in the right fusiform gyrus, corpus callosum and inferior parietal lobule in the group of patients with obsessive-compulsive symptoms (p < 0.05). Conclusions: Our findings increase the understanding of the pathophysiology of schizophrenia and may provide imaging evidence for early diagnosis of COSO or COS.