Curcumin micelles suppress gastric tumor cell growth by upregulating ROS generation, disrupting redox equilibrium and affecting mitochondrial bioenergetics.

Gastric cancer is the fourth most common cancer and the second most frequent cause of cancer death worldwide. Chemotherapy is an important treatment. However, traditional chemotherapy drugs have low bioavailability and targeting ability. Therefore, we developed curcumin-encapsulated micelles for the treatment of gastric cancer and investigated their antitumor efficacy and active mechanism. Gastric cancer cells were treated with different concentrations of curcumin micelles. MTS cell proliferation assays, flow cytometry (FCM), real time cellular analysis (RTCA) and nude mice xenografts were used to evaluate the effects of curcumin micelles on gastric cancer cell growth in vitro and in vivo. Western blotting was performed to analyze the protein levels of the indicated molecules. A Seahorse bioenergetics analyzer was used to investigate alterations in oxygen consumption and the aerobic glycolysis rate. Curcumin micelles significantly inhibited proliferation and colony formation and induced apoptosis in gastric tumor cells compared to the control groups. We further investigated the mechanism of curcumin micelles on gastric tumor cells and demonstrated that curcumin micelles acted on mitochondrial proteins, causing changes in mitochondrial function and affecting mitochondrial bioenergetics. Furthermore, curcumin micelles decreased mitochondrial membrane potential, increased reactive oxygen species (ROS) generation and disrupted redox equilibrium. The nude mouse model verified that curcumin micelle treatment significantly attenuated tumor growth in vivo. Curcumin micelles suppress gastric tumor cell growth in vitro and in vivo. The mechanism may be related to increasing ROS generation, disrupting redox equilibrium and affecting mitochondrial bioenergetics.

Mechanisms Underlying Therapeutic Effects Of Traditional Chinese Medicine On Gastric Cancer.

Gastric cancer (GC) is one of the most common malignant tumors in the world. It is the fourth most common cancer and has the second highest mortality rate globally. Metastasis is an important feature of gastric cancer and is the most common cause of death. Exploring the mechanism underlying the metastasis of gastric cancer and searching for new drug targets has become the focus of several studies. Traditional Chinese medicine may show promise for treatment of gastric cancer. In this review, we report the recent progress in research on the anti-metastasis activity of Chinese medicine, to facilitate clinical development of treatments for gastric cancer.

Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics.

BACKGROUND: Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcumin in regulating cellular bioenergetic processes remains largely unknown. METHODS: Western blotting and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. RTCA, CCK-8 assay, nude mice xenograft assay, and in vivo bioluminescence imaging were used to visualize the effects of curcmin on gastric cancer cell growth in vitro and in vivo. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. RESULTS: Curcumin significantly inhibited gastric tumor cell growth, proliferation and colony formation. We further investigated the role of curcumin in regulating cellular redox homeostasis and demonstrated that curcumin initiated severe cellular apoptosis via disrupting mitochondrial homeostasis, thereby enhancing cellular oxidative stress in gastric cancer cells. Furthermore, curcumin dramatically decreased mtDNA content and DNA polymerase γ (POLG) which contributed to reduced mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion via ROS generation, and POLG knockdown also reduced oxidative phosphorylation (OXPHOS) activity and cellular glycolytic rate which was partially rescued by ROS scavenger NAC, indiating POLG plays an important role in the treatment of gastric cancer. Data in the nude mice model verified that curcumin treatment significantly attenuated tumor growth in vivo. Finally, POLG was up-regulated in human gastric cancer tissues and primary gastric cancer cell growth was notably suppressed due to POLG deficiency. CONCLUSIONS: Together, our data suggest a novel mechanism by which curcumin inhibited gastric tumor growth through excessive ROS generation, resulting in depletion of POLG and mtDNA, and the subsequent disruption of cellular bioenergetics.

[Protective effect of tadalafil against ischemia-reperfusion injury in rats].

OBJECTIVE: To investigate the protective effect of phosphodiesterase type 5 inhibitors (tadalafil) on the testis following testicular ischemia-reperfusion injury in rats. METHODS: Eighty-four healthy adult male SD rats were randomly and equally divided into groups A (sham operation), B (testicular torsion + low-dose tadalafil), C (testicular torsion + high-dose tadalafil), and D (testicular torsion + placebo). Models were established in the latter three groups by 7200 torsion of the right testis for 2 hours. The animals in groups A and B were treated by gavage with tadalafil at the dose of 0. 5 mg per kg per day, those in group C at 2 mg per kg per day, and those in group D with saline at the same dose. After 3, 7, and 14 days of treatment, the torsioned testes were harvested for evaluation of the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in the testis tissue. The pathological changes in the testis were observed under the light microscope. RESULTS: At 3, 7, and 14 days, the SOD activity was (254.46 +/- 7.43), (278.49 +/- 8.33), and (317.99 +/- 3.31) nU/mg prot in group B, and (277.12 +/- 8.80), (309.40 +/- 2.14), and (320.39 +/- 4.72) nU/mg prot in group C, all obviously higher than in D ([223.21 +/- 4.65], [231.45 +/- 4.16] and [248.28 +/- 5.74] nU/mg prot), while the MDA content was lower in the former two groups than in the latter. At 3 and 7 days, the SOD activity was significantly higher and the MDA level significantly lower in group C than in B (both P < 0.01) , while at 14 days, neither showed any remarkable differences between the two groups (P > 0.05). No obvious histopathological change was observed in the testis tissue of group A. At 3 and 7 days, pathological examination of the testis tissue revealed significant differences in the number of seminiferous epithelial layers, testicular histological score, and seminiferous tubule diameter in group B (P < 0.01), but the three indexes at 14 days in group B and at 7 days in group C exhibited no remarkable differences from those at 14 days in group A. CONCLUSION: Tadalafil can alleviate testicular ischemia-reperfusion injury following testis torsion/detorsion in a time- and dose-dependent manner.

Preparation of curcumin micelles and the in vitro and in vivo evaluation for cancer therapy.

Poor water solubility as well as poor bioavailability of curcumin has greatly hindered its applications in cancer therapy. In the present study, a highly water soluble curcumin nano-formulation was developed and its in vivo anti-cancer efficiency in nude BALB/c mouse model was evaluated. Unlike native curcumin, the developed curcumin micelles were quickly dissolved into aqueous solution with significant improvement of water solubility (-10(4) fold increasement compared to its native form). The developed curcumin micelles had a narrow size distribution (18-28 nm) with high drug encapsulation efficiency (85%-95%). The developed curcumin micelles were characterized by X-raydiffraction (XRD), Differential scanning calorimetric (DSC), and Fluorescence spectral analysis. We observed the enhanced stability of curcumin in micelles formulation in phosphate buffer solution (PBS). In vitro cytotoxicity assay indicated that the curcumin micelles was comparatively more effective than native curcumin against various cancer cell lines due to the enhanced cellular uptake of curcumin yet resulting in the apoptosis of cancer cells. Western blotting study revealed that the induction apoptosis of S-65 cancer cells by curcumin micelles was mainly due to the down-regulation of p-Rb, Blc-2, p-AKT expression and caspase-9 activation. In vivo anti-tumor test in nude BALB/c mouse bearing S-65 xenografts indicated the intraperitoneal injection of curcumin micelles (25 mg/kg) could significantly inhibit tumor growth as compared with native curcumin treatment (p < 0.05), which was accompanied by significantly increased apoptosis of tumor cells and diminished vascular endothelial growth factor expression in tumor tissue (p < 0.05).