HIF-1α inhibitor YC-1 suppresses triple-negative breast cancer growth and angiogenesis by targeting PlGF/VEGFR1-induced macrophage polarization.

Triple negative breast cancer (TNBC) is an invasive and metastatic phenotype of breast cancer with limited treatment options. Published studies have demonstrated an inhibitory effect of HIF-α inhibition by its inhibitor YC-1 (lificiguat) on growth and angiogenesis of TNBC. However, the underlying mechanism remains poorly understood. In the current paper, our results show that HIF-1α inhibitor significantly inhibited TNBC growth by increasing cellular apoptosis and decreasing MVD, independent of a cell-autonomous mechanism in both endothelial and tumor cells. Genetic screening and in vivo experiments showed that a large number of M2-polarized TAMs accumulated in the hypoxic peri-necrotic region (PNR), where placental growth factor (PlGF) and its ligand, vascular endothelial growth factor receptor-1 (VEGFR-1) were upregulated. Furthermore, YC-1 skewed the polarization of TAMs away from M2 to M1 phenotype, therefore inhibiting TNBC angiogenesis and growth. This effect was further abrogated by VEGFR-1 neutralization and TAM depletion following clodronate liposome injection. These findings provide preclinical evidence for an indirect mechanism underlying YC-1-induced suppression of TNBC growth and angiogenesis, thereby offering a treatment option for TNBC.

Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity / 药物分析学报

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed inde-pendently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endo-thelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

Effect of different combined antihypertensive regimen on the erectile function in male hypertensive patients / 中华心血管病杂志

<p><b>OBJECTIVE</b>To compare the effects of felodipine combined irbesartan regimen with that of felodipine combined metoprolol regimen on the sexual function in male hypertensive patients.</p><p><b>METHOD</b>One hundred and twenty-three male hypertensive patients (age 25 to 60) were randomly assigned to felodipine (5 mg/d) plus irbesartan (150 mg/d, n = 64) group and felodipine (5 mg/d) plus metoprolol (47.5 mg/d, n = 59) group. Dosage of felodipine were doubled after 4 weeks if the blood pressure were > or = 140/ 90 mm Hg (1 mm Hg = 0.133 kPa). At the baseline and post 24th week treatment, sexual function of patients was assessed by the International Index of Erectile Function (IIEF) Questionaire. Serum testosterone (T), sex hormone binding globulin (SHBG), 4-hydroxynonenal (HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and Malonaldehyde (MDA) were measured by Radioimmunoassay (RIA), ELISA and TBA respectively.</p><p><b>RESULTS</b>Total prevalence of erectile dysfunction (ED), T, SHBG and HNE were similar between pre- and post-treatment in two groups (P > 0.05). On the other hand, the scores of the mild ED and sexual desire (SD) were improved and both serum 8-OHdG and MDA in patients with ED decreased [(146.02 +/- 60.54) ng/L vs. (139.89 +/- 62.03) ng/L, P = 0.048 and (6.59 +/- 1.75) micromol/L vs. (5.51 +/- 1.65) micromol/L, P = 0.039] in Felodipine plus Irbesartan group.</p><p><b>CONCLUSION</b>The results suggested that Felodipine + Irbesartan regimen may be superior to Felodipine + metoprolol regimen for male hypertensive patients with mild ED.</p>

Effect between felodipine plus irbesartan and felodipine plus metoprolol regimen on the sexual function in young and middle-aged women with hypertension / 中华心血管病杂志

<p><b>OBJECTIVE</b>To compare the effects between felodipine plus irbesartan and felodipine plus metoprolol regimen on blood pressure and the sexual function in young and middle-aged hypertensive women.</p><p><b>METHODS</b>In this prospective, randomized, parallelized, controlled and fixed combined therapy trial, 99 female patients (aged 18 to 60) with grade 1 and grade 2 hypertension (BP ≥ 140/90 mm Hg and < 179/109 mm Hg, 1 mm Hg = 0.133 kPa) were assigned to felodipine 5 mg q.d + irbesartan 150 mg q.d (F + I group, n = 49) and felodipine 5 mg q.d + metoprolol 47.5 mg q.d (F + M group, n = 50) group. Target blood pressure was < 140/90 mm Hg. The female sexual function index (FSFI) questionnaire, levels of serum estradiol and testosterone were assessed. Female sexual dysfunction was defined as a FSFI score of less than 25.5. Patients were followed up for 24 weeks.</p><p><b>RESULTS</b>The rate of achieving blood pressure goal between 2 groups was similar at the 4th, 8th, 12th and 24th weeks respectively (42.9% vs. 62.0% at 4th week, 89.8% vs. 90.0% at 8th week, 93.9% vs. 94.0% at 12th week, 98.0% vs. 96.0% at 24th week, P > 0.05). Compared to baseline, scores for the items related to "desire" and "arousal" were significantly improved (P < 0.05), the level of the serum estradiol was significantly elevated [(50.3 ± 37.4) pg/L vs. (54.4 ± 10.8) pg/L before menopause, (18.4 ± 2.9) pg/L vs. (20.2 ± 3.1)pg/L after menopause, P < 0.05] and the level of the serum testosterone was significantly decreased [(722.8 ± 277.1) ng/L vs. (650.0 ± 156.0) ng/L before menopause, (841.2 ± 279.3) ng/L vs. (761.9 ± 197.8) ng/L after menopause, P < 0.05] in the F + I group, while scores for the items related to "sexual desire" and "lubrication" were statistically reduced (P < 0.01), the concentration of the serum estradiol was significantly reduced [(57.4 ± 9.7) pg/L vs. (51.1 ± 12.1) pg/L before menopause, (19.8 ± 2.3) pg/L vs. (17.8 ± 3.3) pg/L after menopause, P < 0.01] and the level of the serum testosterone was significantly increased [(775.6 ± 217.8) ng/L vs. (886.0 ± 186.4) ng/L before menopause, (812.5 ± 311.3) ng/L vs. (914.4 ± 300.2) ng/L after menopause, P < 0.01] in the F + M group. FSFI score was negatively correlated with age and systolic blood pressure levels.</p><p><b>CONCLUSION</b>felodipine plus irbesartan or metoprolol for 24 weeks equally reduced blood pressure and the former regimen is superior to the latter on sexual function improvement in this patient cohort.</p>