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The aim of this study was to explore whether rhein could enhance the effects of pemetrexed (PTX) on the therapy of non‐small‐cell lung cancer (NSCLC) and to clarify the associated molecular mechanism. Our study shows that rhein in combination with PTX could obviously increase the systemic exposure of PTX in rats, which would be mediated by the inhibition of organic anion transporters (OATs). Furthermore, the toxicity of PTX was significantly raised by rhein in A549 cells in a concentration‐dependent manner. Concomitant administration of rhein and PTX‐induced cell apoptosis compared with PTX alone in flow cytometry assays, which was further validated by the protein expressions of the apoptotic markers B‐cell lymphoma‐2/Bcl‐2‐associated x (Bcl‐2/Bax) and Cleaved‐Caspase3 (Cl‐Caspase3). Meanwhile, the results of monodansylcadaverine (MDC) dyeing experiments showed that PTX‐induced autophagy could be enhanced by combination therapy with rhein in A549 cells. Western blot analysis indicated that the synergistic effect of rhein on PTX‐mediated autophagy may be interrelated to PI3K–AKT–mTOR pathway inhibition and to the enhancement of p‐AMPK and light chain 3‐II (LC3‐II) protein levels. From these findings, it could be surmised that rhein enhanced the antitumor activity of PTX through influencing autophagy and apoptosis by modulating the PI3K–AKT–mTOR pathway and Bcl‐2 family of proteins in A549 cells. Our findings demonstrated that the potential application of rhein as a candidate drug in combination with PTX is promising for treatment of the human lung cancer. [ABSTRACT FROM AUTHOR]

Glucocorticoid‐induced osteoporosis (GIO) is a secondary osteoporosis with extensive use of glucocorticoids (GCs). GCs can increase bone fragility and fracture via inhibiting osteoblastic proliferation and differentiation. Luteolin (LUT), a kind of plant flavonoid, has been reported to exhibit the antioxidant activity, but the effects of LUT on GIO still remain unclear. This study aimed to investigate the effects of LUT on GIO both in vivo and in vitro and elaborate the potential molecular mechanisms. LUT increased the superoxide dismutase activity, glutathione level and decreased reactive oxygen species (ROS) level and lactate dehydrogenase release in GIO. Meanwhile, LUT decreased caspase‐3, caspase‐9, and Bax protein expressions and increased Bcl‐2 protein expression in GIO. LUT increased the ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor‐κB Ligand (RANKL) messenger RNA (mRNA) expression and mRNA expression levels of osteogenic markers, including runt‐related transcription factor 2, osterix, collagen type I, and osteocalcin. LUT also enhanced the extracellular signal‐regulated kinases (ERK) phosphorylation, glycogen synthase kinase 3β (GSK‐3β) phosphorylation, mRNA expression levels of lipoprotein‐receptor‐related protein 5 (Lrp‐5) and β‐catenin. Further study revealed that Lrp‐5 small interfering RNA (siRNA)and ERK‐siRNA reduced the effects of LUT on GSK‐3β phosphorylation, alkaline phosphatase (ALP) activity and the ratio of OPG/RANKL mRNA expression. Moreover, ERK‐siRNA decreased Lrp‐5 mRNA expression in vitro. These results indicated that LUT promoted proliferation by attenuating oxidative stress and promoted osteoblastic differentiation by regulating the ERK/Lrp‐5/GSK‐3β pathway in GIO. This study may bring to light the possible mechanisms involved in the action of LUT in GIO treatment, and benefit for further research on GIO. Luteolin (LUT) could inhibit osteoblastic apoptosis via inhibiting oxidative stress in glucocorticoid‐induced osteoporosis (GIO). Moreover, LUT could promote osteoblastic differentiation via the extracellular signal‐regulated kinases (ERK)/lipoprotein‐receptor‐related protein 5 (Lrp‐5)/glycogen synthase kinase 3β (GSK‐3β) signaling pathway in GIO. [ABSTRACT FROM AUTHOR]

Though the advancement of chemotherapy drugs alleviates the progress of cancer, long‐term therapy with anticancer agents gradually leads to acquired multidrug resistance (MDR), which limits the survival outcomes in patients. It was shown that dihydromyricetin (DMY) could partly reverse MDR by suppressing P‐glycoprotein (P‐gp) and soluble resistance‐related calcium‐binding protein (SORCIN) independently. To reverse MDR more effectively, a new strategy was raised, that is, circumventing MDR by the coadministration of DMY and ondansetron (OND), a common antiemetic drug, during cancer chemotherapy. Meanwhile, the interior relation between P‐gp and SORCIN was also revealed. The combination of DMY and OND strongly enhanced antiproliferative efficiency of adriamycin (ADR) because of the increasing accumulation of ADR in K562/ADR‐resistant cell line. DMY could downregulate the expression of SORCIN and P‐gp via the ERK/Akt pathways, whereas OND could not. In addition, it was proved that SORCIN suppressed ERK and Akt to inhibit P‐gp by the silence of SORCIN, however, not vice versa. Finally, the combination of DMY, OND, and ADR led to G2/M cell cycle arrest and apoptosis via resuming P53 function and restraining relevant proteins expression. These fundamental findings provided a promising approach for further treatment of MDR. Soluble resistance‐related calcium‐binding protein suppressed expression of P‐glycoprotein via ERK/Akt signaling pathways. Coadministration of dihydromyricetin and ondansetron could strongly enhance the antiproliferative efficiency of adriamycin (ADR) by promoting ADR‐induced G2/M cell cycle arrest and apoptosis. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is the fourth leading cause of cancer‐related death worldwide. Advances in therapeutic strategies such as chemotherapy have improved the clinical outcomes for pancreatic cancer patients. However, developing new therapeutic compounds against pancreatic cancer is still urgent due to the poor prognosis. Here, we show that SZC015, an oleanolic acid derivative, exhibits potent inhibitory effect on both pancreatic cancer cells in vitro and the corresponding xenograft tumors in vivo. Mechanistically, the activation of intrinsic apoptosis and G1 phase arrest resulting from mitochondria damage caused by SZC015 contribute significantly to the anticancer effects of SZC015. SZC015 also has remarkably inhibitory effects on the transcription factors that are extensively activated in pancreatic cancer tissues. As a constitutively activated transcription factor in pancreatic cancer, the nuclear factor κB is highly suppressed after SZC015 treatment in vitro or administration in vivo. Based on the bioinformatics analysis of microarray data, we validate that JAK2/STAT3 signaling is indeed activated in the human pancreatic cancer tissues and SZC015 also shows inhibitory effect on this signaling both in vitro and in vivo. These data suggest the potent effects of SZC015 on pancreatic cancer and also provided novel insights into the mechanisms of SZC015 as a new potent candidate for treating pancreatic cancer. SZC015, an oleanolic acid derivative, exhibits inhibitory effect on pancreatic cancer both in vitro and in vivo. SZC015‐damaged mitochondria generates excessive reactive oxygen species that eventually impairs the cell proliferation of pancreatic cancer. Two types of vital transcriptional signaling, including nuclear factor κB and STAT3, in pancreatic cancer are highly suppressed by SZC015 both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Recently, a new target Ca2+-binding protein SORCIN was reported to participate in multidrug resistance (MDR)in cancer.Herewe aim to investigatewhether dihydromyricetin (DMY), a dihydroflavonol compound with anti-inflamatory, anti-oxidant, anti-bacterial and anti-tumor actions, reverses MDR in MCF-7/ADR and K562/ADR and to elucidate its potential molecular mechanism. DMY enhanced cytotoxicity of adriamycin (ADR) by downregulatingMDR1 mRNA and P-gp expression through MAPK/ERK pathway and also inhibiting the function of P-gp significantly.Meanwhile,DMYdecreasedmRNA and protein expression of SORCIN, which resulted in elevating intracellular free Ca2+. Finally, we investigated co-administration ADR with DMY remarkably increased ADR-induced apoptosis. Further study showed DMY elevated ROS levels and caspase-12 protein expression, which signal apoptosis in endoplasmic reticulum. At the same time, proteins related to mitochondrial apoptosis were also changed such as Bcl-2, Bax, caspase-3, caspase-9, and PARP. Finally, nudemicemodel also demonstrated thatDMY strengthened anti-tumor activity of ADR in vivo. In conclusion, DMY reverses MDR by downregulating P-gp, SORCIN expression and increasing freeCa2+, aswell as, inducing apoptosis inMCF-7/ ADR and K562/ADR. These fundamental findings provide evidence for further clinical research in application of DMY as an assistant agent in the treatment of cancer. [ABSTRACT FROM AUTHOR]

Recently, a new target Ca 2+ -binding protein SORCIN was reported to participate in multidrug resistance (MDR) in cancer. Here we aim to investigate whether dihydromyricetin (DMY), a dihydroflavonol compound with anti-inflamatory, anti-oxidant, anti-bacterial and anti-tumor actions, reverses MDR in MCF-7/ADR and K562/ADR and to elucidate its potential molecular mechanism. DMY enhanced cytotoxicity of adriamycin (ADR) by downregulating MDR1 mRNA and P-gp expression through MAPK/ERK pathway and also inhibiting the function of P-gp significantly. Meanwhile, DMY decreased mRNA and protein expression of SORCIN, which resulted in elevating intracellular free Ca 2+ . Finally, we investigated co-administration ADR with DMY remarkably increased ADR-induced apoptosis. Further study showed DMY elevated ROS levels and caspase-12 protein expression, which signal apoptosis in endoplasmic reticulum. At the same time, proteins related to mitochondrial apoptosis were also changed such as Bcl-2, Bax, caspase-3, caspase-9, and PARP. Finally, nude mice model also demonstrated that DMY strengthened anti-tumor activity of ADR in vivo. In conclusion, DMY reverses MDR by downregulating P-gp, SORCIN expression and increasing free Ca 2+ , as well as, inducing apoptosis in MCF-7/ADR and K562/ADR. These fundamental findings provide evidence for further clinical research in application of DMY as an assistant agent in the treatment of cancer., (© 2017 Wiley Periodicals, Inc.)