Red ginseng polysaccharide promotes ferroptosis in gastric cancer cells by inhibiting PI3K/Akt pathway through down-regulation of AQP3.

OBJECTIVE: This study aims to investigate the effect of red ginseng polysaccharide (RGP) on gastric cancer (GC) development and explore its mechanism. METHODS: GC cell lines AGS were treated with varying concentrations of RGP (50, 100, and 200 µg/mL). AGS cells treated with 200 µg/mL RGP were transfected with aquaporin 3 (AQP3) overexpression vector. Cell proliferation, viability, and apoptosis were evaluated by MTT, colony formation assay, and flow cytometry, respectively. Real-time quantitative reverse transcription PCR (qRT-PCR) was used to detect the expression of AQP3. The levels of Fe2+, malondialdehyde, and lactate dehydrogenase were measured using their respective detection kits, and the reactive oxygen species levels was determined by probe 2',7'-dichlorodihydrofluorescein diacetate. The expression of ferroptosis-related protein and PI3K/Akt pathway-related protein were assessed by western blot. In vivo experiments in nude mice were performed and the mice were divided into four groups (n = 5/group) which gavage administrated with 150 mg/kg normal saline, and 75, 150, 300 mg/kg RGP, respectively. Their tumor weight and volume were recorded. RESULTS: RGP treatment effectively inhibited the proliferation and viability of AGS cells in a dosage-dependent manner and induced apoptosis. It induced ferroptosis in AGS cells, as well as inhibiting the expression of PI3K/Akt-related proteins. AQP3 overexpression could reversed the effect of RGP treatment on ferroptosis. Confirmatory in vivo experiments showed that RGP could reduce the growth of implanted tumor, with increased RGP concentration resulting in greater tumor inhibitory effects. CONCLUSION: RGP might have therapeutic potential against GC, effectively inhibiting the proliferation and viability of AGS cells.

Defeating relapsed and refractory malignancies through a nano-enabled mitochondria-mediated respiratory inhibition and damage pathway.

Hypoxia, which frequently reduces the sensitivity to many therapeutic interventions, including chemotherapy, radiotherapy and phototherapy, has been acknowledged as an important reason for poor prognosis. Burgeoning evidences have proved that the tumor hypoxia microenvironment can reduce the therapeutic effect on tumor through inhibiting the drug efficacy, limiting immune cell infiltration of tumors and accelerating tumor recurrence and metastasis. However, the relationship between oxygen supply and the proliferation of cancer cells is still ambiguous and argued. Different from the current commonly used oxygen supply strategies, this study concentrated on the reduction of endogenous oxygen consumption. Specifically, a novel photosensitizers (IR780) and metformin are packaged in PEG-PCL liposomes. Once such nanoparticles accumulated in tumor tissues, the tumor foci were irradiated through 808 nm laser, generated ROS to further release metformin and IR780. Metformin can directly inhibit the activity of complex Ⅰ in the mitochondrial electron transport chain, thus performed a potent inhibitor of cell respiration. After overcoming tumor hypoxia, the combination of mitochondria-targeted photodynamic therapy (PDT) and photothermic therapy (PTT) via IR780 may achieve superior synergistically therapeutic efficacy. Benefit from excellent characteristics of IR780, such synergistic PDT PTT with the inhibition of mitochondrial respiration can be monitored through near-infrared/photoacoustic dual-modal imaging. Such a conception of reducing endogenous oxygen consumption may offer a novel way to solve the important puzzles of hypoxia-induced tumor resistance to therapeutic interventions, not limited to phototherapy.

Self-generating oxygen enhanced mitochondrion-targeted photodynamic therapy for tumor treatment with hypoxia scavenging.

Tumor hypoxia is an important reason for the limited therapeutic efficacy of photodynamic therapy (PDT) because of the oxygen requirement of the therapeutic process. PDT consumes tissue oxygen and destroys tumor vasculature, further hampering its own efficacy in promoting tumor deterioration. Therefore, overcoming the photodynamic exacerbation of tumor hypoxia is urgent. Methods: Herein, we report a photodynamic nanoparticle with sustainable hypoxia remission skills by both intratumoral H2O2 catalysis and targeted mitochondrial destruction. The Mn3O4@MSNs@IR780 nanoparticles are formed by absorbing a photosensitizer (IR780) into 90 nm mesoporous silica nanoparticles (MSNs) and capping the surface pores with 5 nm Mn3O4 nanoparticles. Results: These Mn3O4 nanoparticles can accumulate in tumors and respond to the H2O2-enriched tumor microenvironment by decomposing and catalyzing H2O2 into O2. Afterwards, IR780 is released and activated, spontaneously targeting the mitochondria due to its natural mitochondrial affinity. Under laser irradiation, this self-generated oxygen-enhanced PDT can destroy mitochondria and inhibit cell respiration, resulting in sustainable hypoxia remission in tumor tissues and consequently enhancing the therapeutic outcome. In vitro experiments suggest that Mn3O4@MSNs@IR780 exhibited highly mitochondrion-targeted properties and could sustainably inhibit tumor hypoxia. Additionally, the highest photoacoustic signal of HbO2 with the lowest Hb was observed in tumors from mice after PDT, indicating that these nanoparticles can also prevent tumor hypoxia in vivo. Conclusion: Taken together, our study indicated a new approach for overcoming the sustainable hypoxia limitation in traditional PDT by targeted oxygen supplementation and mitochondria destruction.

Synergistic anticancer effects of polyphyllin I and evodiamine on freshly-removed human gastric tumors.

OBJECTIVE: The present study was designed to examine the anticancer effect of Traditional Chinese Medicine of polyphyllin I (PPI) and evodiamine (EVO) on freshly-removed gastric tumor tissues. METHODS: Sixty freshly-removed gastric tumor tissues were collected. Their sensitivity to PPI, EVO, platinum (Pt), 5-FU, irinotecan (CPT-11) were determined by histoculture drug response assay (HDRA). Those samples were also formalin-fixed and paraffin-embedded, which were used to examine the mRNA expression levels of aprataxin(APTX), excision repair cross-complementing 1(ERCC1), thymidylate synthase(TS) and topoisomerase I(TOPO1) by quantitative RT-PCR. The association of the gene expression levels and in vitro sensitivity were analyzed. RESULTS: PPI, EVO, Pt, 5-FU and CPT-11 had anticancer effects on the freshly-removed gastric tumor tissues with average inhibition rates of 20.64%±14.25% for PPI, 21.14%±13.43% for EVO, 50.57%±22.37% for Pt, 53.54%±22.03% for 5-FU, and 39.33%±24.79% for CPT-11, respectively. Combination of PPI and Pt, EVO and Pt, EVO and 5-FU had higher inhibition rates than any single drug of them (P<0.001, P = 0.028, P = 0.017, respectively). The mRNA expression levels of ERCC1 were correlated with Pt sensitivity (rho = -0.645, P<0.001); the mRNA expression levels of TS were correlated with 5-FU sensitivity (rho = -0.803, P<0.001). There were also weak but significant correlations between APTX mRNA expression levels and CPT-11 sensitivity (rho = -0.376, P = 0.017) or EVO sensitivity (rho = -0.322, P = 0.036). ERCC1 mRNA expression levels was markedly suppressed by the presentation of PPI (P = 0.001) and slightly suppressed by the presentation of EVO (P = 0.04); whereas, TS mRNA expression levels was markedly decreased by the presentation of EVO (P = 0.017) and slightly decreased by the presentation of PPI (P = 0.047). CONCLUSION: PPI and EVO both could inhibit the activity of freshly-removed gastric tumor, and they could enhance the anticancer effect of Pt and 5-FU by reducing the mRNA expression levels of ERCC1 and TS.