Cancer multidrug resistance (MDR) impairs the therapeutic efficacy of various chemotherapeutics. Novel approaches, particularly the development of MDR reversal agents, are critically needed to address this challenge. This study demonstrates that tenacissoside I (TI), a compound isolated from Marsdenia tenacissima (Roxb.) Wight et Arn, traditionally used in clinical practice as an ethnic medicine for cancer treatment, exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells. TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin (DOX) and paclitaxel (PAC) by downregulating ABCB1 expression and reducing ABCB1 drug transport function. Mechanistically, protein arginine methyltransferase 1 (PRMT1), whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues, was differentially expressed in TI-treated SW620/AD300 cells. SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine (aDMA) and enhanced PRMT1-EGFR interaction compared to their parental cells. Moreover, TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR, PRMT1-EGFR interaction, and EGFR downstream signaling in SW620/AD300 and KBV200 cells. These effects were significantly reversed by PRMT1 overexpression. Additionally, TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities. This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR, suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
Humans ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors* ; Drug Resistance, Neoplasm/drug effects* ; ErbB Receptors/genetics* ; Animals ; Cell Line, Tumor ; Drug Resistance, Multiple/drug effects* ; Methylation/drug effects* ; Saponins/administration & dosage* ; Mice ; Mice, Nude ; Mice, Inbred BALB C ; ATP Binding Cassette Transporter, Subfamily B/genetics* ; Doxorubicin/pharmacology* ; Paclitaxel/pharmacology* ; Female ; Repressor Proteins

Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia.However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/ S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.

Objective To study the autophagy of human glioblastoma SF295 cells induced by sponge-derived triterpenoid Stellittin B (Stel B) and to discuss the related mechanism. Methods The proliferation inhibitory activity of Stel B on SF295 cells was studied by WST-8 assay. The autophagy effect induced by Stel B on SF295 cells was evaluated bya variety of experimental techniques, including MDC staining, Western Blot assay, and mRFP-GFP-LC3 plasmid transfection method.The activity of Stel B on the representative signal proteins in PI3K/Akt/mTOR pathway in SF295 cells was examined by Western Blot. The anti-tumor activity of Stel B was detected by WST-8 assay after blocking autophagy by autophagy inhibitor chloroquine. Results Stel B could significantly inhibit the proliferation of SF295 cells with IC50 value as 0.026 μmol/L. Plenty of autophagosome was found in Stel B treated A549 cells by MDC staining. The expression of autophagy marker proteins including LC3B-II increased. The confocal microscopy results showed that Stel B promoted autophagosome forming and inhibitedthe fusion of autophagosome with lysosome. The Western Blot results showed that Stel B inhibited the expression of PI3K-p110 protein in SF295 cells and decreased the phosphorylation level of Akt and mTOR.The inhibitory effects of Stel B with different concentrations on SF295 cells were all enhanced by the inhibition of autophagy with chloroquine, and the differences were statistically significant (all P<0.05). Conclusion Stel B can induce SF295 cells autophagy via blocking PI3K/Akt/mTOR pathway. This autophagy effect is beneficial to the survival of SF295 cells. The antitumor activity of Stel B can be enhanced by a combination of autophagy inhibitors.

The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in human cancers. Class I PI3Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin (mTOR) to play key roles in carcinogenesis. Therefore, PI3K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3K inhibitor for cancer therapy. Dozens of other PI3K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers, etc. This review provides an introduction to PI3K and summarizes key advances in the development of PI3K inhibitors.

Objective To introduce and analyze the status of tumor multidisciplinary team (MDT) model application in primary hospitals.Methods MDT discussion decision-making and implementation of Nanpi People's Hospital from June 2013 to July 2015 were retrospectively analyzed.Results A total of 251 cases were recruited into the MDT discussion.Among them,233 primarily diagnosed cases reached MDT decision-making and 159 cases took the decision,118 cases achieved the purpose (74.2％),41 cases failed (25.8％).Yet in 74 cases not following the decision,11 cases achieved the desired purpose (14.9％),while 63 cases didn't meet the desired purpose (85.1％),the difference was statistically significant (x2 =71.97,P ＜ 0.01).Ultrasound interventional biopsy,enhanced CT scan,CT guided puncture,intraoperative frozen section examination in malignant tumor patients had significantly increased after MDT applied,the difference was statistically significant (all P ＜ 0.05).The annual new rural cooperative medical system referral rate in malignant tumor patients dropped sharply (x2 =19.86,P ＜ 0.01) Conclusions Doctors and cancer patients can benefit from MDT diagnosis and treatment model,which is worth generalization.

Erythropoietin (EPO) is an active glycoprotein synthesized by kidney. The physiological function of regulat?ing the synthesis of erythrocytes by EPO makes it as a clinical drug for treatment of anemia resulted from chronic kidney fail?ure. However, its short biological half-life makes frequent administration, which limits its wide clinical utility since the tough burden and pain on patients. Therefore, the development of EPO derivatives with good efficacy, less adverse reaction and long duration has been a hot spot in the field during several decades. There are currently many different variants of EPO derivatives including erythropoiesis stimulating agents (ESAs) on the market. This article aims to summarize the recent re?search progress in the development of erythropoietin derivatives, specially focusing on EPO mimetic peptides (EMP).

OBJECTIVETo explore the association between occupational stress and other socio-psychological factors and work-related unintentional injury in off-shore oil production.

METHODSA cross-sectional survey was conducted among 561 Chinese off-shore oil workers. They were inquired with a self-administered questionnaire involving in socio-demographic characteristics, occupational stress, type A behavior personnel, social support and coping style, and work-related unintentional injury in the past year.

RESULTSSeventy-six (13.5%) workers experienced work-related unintentional injury for once time or more in the past year. A total 141 number of person-times were counted including 18 person-times being serious injury, 26 person-times moderate, and 97 person-times light. After adjustment for age, educational level, marital status, duration of off-shore work and job title, logistic regression indicated that perceived stress from "management problem and relationship with others" were significantly associated with work-related unintentional injuries in the past year (OR = 1.33, 95% CI: 1.05-1.68; P < 0.05). Workers lack of emotional support from friends seemed to less reporting on work-related unintentional injuries (OR = 0.37, 95% CI: 0.22-0.63).

CONCLUSIONThe results implied emphasizing on that the training and guidance as well as better cooperation among the workers might reduce work-related unintentional injuries in off-shore oil industry.

Accidents, Occupational ; prevention & control ; statistics & numerical data ; Adult ; Fuel Oils ; Humans ; Male ; Middle Aged ; Occupational Diseases ; complications ; Stress, Psychological ; complications ; Wounds and Injuries ; etiology ; prevention & control

Aim To study the change of blood pressure in 1079 workers for fifteen years and the effect of anti-hypertension drugs therapy. Methods We investigated the blood pressure of 1079 workers who were enrolled in six organizations in the year 1983 and 1998 respectively. Results During the 15 years: (1)Mean value of blood pressure: systolic blood pressure increased 22 mmHg in man and 16.9 mmHg in women; diastolic blood pressure increased 9 mmHg in man and 12.7 mmHg in women (P<0.05);(2)The incidence of hypertension increased by 25.03% in man and 28.28% in women;(3)The prevalence rate of hypertension is 27.9 percent in people with initially normal blood pressure (1.86%/y) and 72.6 percent in initially broder line hypertension (4.84%/y);(4)The control rate of hypertension is 2.9 percent;(5)The incidence of stroke is highly related to hypertension (P<0.001);(6)46.6 percent patients had a regular drug therapy, mainly reserpini complex(25.2%);(7)Drug therapy has no obviously effect of the control of hypertension and the incidence of stroke. Conclusion Both the mean value of BP and the incidence of hypertension were increased with age. The control rate of hypertension was low and the drug therapy shows little advantage. We should do mach more works to popularize the knowledge of the prevention of hypertension. Improve people's self-prevention. Regular cheek should be given to the hypertension patients.