Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy.

PURPOSE: Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy. METHODS: We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism. RESULTS: Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays. CONCLUSION: Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.

Verapamil modulates NFAT2 to inhibit tumor growth and potentiates PD1ab immune checkpoint inhibitor therapy in cervical cancer treatment.

PURPOSE: Current evidence suggests a high co-prevalence of hypertension and cervical cancer. Accordingly, blood pressure control is indicated during anti-tumor drug therapy in this patient population. Over the past few years, immunotherapy has made great strides in treating different cancers. However, the role and clinical significance of verapamil as a first-line anti-hypertensive drug during immunotherapy remain poorly understood, emphasizing the need for further studies. METHODS: Murine cervical cancer models were employed to assess the effect of verapamil monotherapy and combination with PD1ab. Immunohistochemistry was conducted to quantify the abundance of CD8+ T cell and Ki67+ cells. Several in-vitro and in-vivo assays were used to study the effects of verapamil and explore the preliminary mechanism. RESULTS: Monotherapy with verapamil or PD1ab immune checkpoint inhibitor significantly suppressed the growth of subcutaneously grafted U14 cells in WT BABL/c mice, respectively, with increased survival time of mice. Consistent results were observed in the melanoma model. Furthermore, we substantiated that verapamil significantly impaired tumor proliferation and migration of SiHa human cervical cancer cells in vitro and in vivo. In silico analysis using TCGA data revealed that NFAT2 expression negatively correlated with patient survival. The CCK8 assay revealed that verapamil abrogated the stimulatory effect of NFAT2 after knockdown of NFAT2. CONCLUSIONS: Our results suggest that verapamil inhibits tumor growth by modulating NFAT2 expression and enhancing tumor immune responses to PD1ab, which can be harnessed for cervical cancer therapy, especially for patients with comorbid hypertension. Indeed, further clinical trials are warranted to increase the robustness of our findings.

Luteolin inhibits angiogenesis of the M2­like TAMs via the downregulation of hypoxia inducible factor­1α and the STAT3 signalling pathway under hypoxia.

The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour­associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2­like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia­inducible factor­1α (HIF­1α), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase­9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF­1 and phosphorylated­signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2­like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF­1α and STAT3 signalling pathways.

HNRNPA2B1 regulates the epithelial-mesenchymal transition in pancreatic cancer cells through the ERK/snail signalling pathway.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is closely related to tumour occurrence and development, oncogene expression, apoptosis inhibition and invasion and metastasis capacities. However, its function in the epithelial-mesenchymal transition (EMT) of pancreatic cancer is not fully understood. METHODS: By comparing various wild-type pancreatic cancer cell lines, we determined which have a higher expression level of HNRNPA2B1 accompanied by the higher expression of N-cadherin and vimentin and lower expression of E-cadherin. Therefore, to elucidate the role of HNRNPA2B1 in EMT, we generated models of HNRNPA2B1 knockdown and overexpression in different types of pancreatic cancer cell lines (MIA Paca-2, PANC-1 and Patu-8988) and examined changes in expression of EMT-related factors, including CDH1, CDH2, vimentin and snail. RESULTS: The results show that HNRNPA2B1 promotes EMT development by down-regulating E-cadherin and up-regulating N-cadherin and vimentin, and also stimulates the invasion capacity and inhibits viability in human pancreatic cancer cell lines, the similar results in vivo experiments. Moreover, we found that HNRNPA2B1 likely regulates EMT progression in pancreatic carcinoma via the ERK/snail signalling pathway. CONCLUSIONS: The results of this work suggest that HNRNPA2B1 inhibition has potential antitumour effects, which warrants in-depth investigation.