SQAP, an acyl sulfoquinovosyl derivative, suppresses expression of histone deacetylase and induces cell death of cancer cells under hypoxic conditions

Sulfoglycolipid, SQAP, is a radiosensitizing agent that makes tumor cells more sensitive to radiation therapy. A previous study revealed that SQAP induced the degradation of hypoxia-inducible factor-1α (HIF-1α) and inhibited angiogenesis in a hepatoma model mouse. Herein, we examined the biological activities of SQAP against hepatocarcinoma cells under low oxygen conditions. Cell growth inhibition of SQAP under hypoxic conditions was significantly higher than that under normoxic conditions. In addition, SQAP was found to impair the expression of histone deacetylase (HDAC) under low oxygen conditions. Our present data suggested that SQAP induced the degradation of HIF-1α and then decreased the expression of HDAC1. Unlike known HDAC inhibitors, SQAP increased the acetylation level of histone in cells without inhibition of enzymatic activity of HDACs. Our data demonstrated hypoxia-specific unique properties of SQAP.

Plasmodium infection inhibits tumor angiogenesis through effects on tumor-associated macrophages in a murine implanted hepatoma model

Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in China. The lack of an effective treatment for this disease results in a high recurrence rate in patients who undergo radical tumor resection, and the 5-year survival rate of these patients remains low. Our previous studies demonstrated that Plasmodium infection provides a potent antitumor effect by inducing innate and adaptive immunity in a murine Lewis lung carcinoma (LLC) model. Methods This study aimed to investigate the inhibitory effect of Plasmodium infection on hepatocellular carcinoma in mice, and various techniques for gene expression analysis were used to identify possible signal regulation mechanisms. Results We found that Plasmodium infection efficiently inhibited tumor progression and prolonged survival in tumor-bearing mice, which served as a murine implanted hepatoma model. The inhibition of tumor progression by Plasmodium infection was related to suppression of tumor angiogenesis within the tumor tissue and decreased infiltration of tumor-associated macrophages (TAMs). Further study demonstrated that matrix metalloprotease 9 (MMP-9) produced by TAMs contributed to tumor angiogenesis in the tumor tissue and that the parasite-induced reduction in MMP-9 expression in TAMs resulted in the suppression of tumor angiogenesis. A mechanistic study revealed that the Plasmodium-derived hemozoin (HZ) that accumulated in TAMs inhibited IGF-1 signaling through the PI3-K and MAPK signaling pathways and thereby decreased the expression of MMP-9 in TAMs. Conclusions Our study suggests that this novel approach of inhibiting tumor angiogenesis by Plasmodium infection is of high importance for the development of new therapies for cancer patients.

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.

Plasmodium infection inhibits tumor angiogenesis through effects on tumor-associated macrophages in a murine implanted hepatoma model

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in China. The lack of an effective treatment for this disease results in a high recurrence rate in patients who undergo radical tumor resection, and the 5-year survival rate of these patients remains low. Our previous studies demonstrated that Plasmodium infection provides a potent antitumor effect by inducing innate and adaptive immunity in a murine Lewis lung carcinoma (LLC) model. Methods: This study aimed to investigate the inhibitory effect of Plasmodium infection on hepatocellular carcinoma in mice, and various techniques for gene expression analysis were used to identify possible signal regulation mechanisms. Results: We found that Plasmodium infection efficiently inhibited tumor progression and prolonged survival in tumor-bearing mice, which served as a murine implanted hepatoma model. The inhibition of tumor progression by Plasmodium infection was related to suppression of tumor angiogenesis within the tumor tissue and decreased infiltration of tumor-associated macrophages (TAMs). Further study demonstrated that matrix metalloprotease 9 (MMP-9) produced by TAMs contributed to tumor angiogenesis in tumor tissue and that the parasite-induced reduction in MMP-9 expression in TAMs resulted in the suppression of tumor angiogenesis. A mechanistic study revealed that the Plasmodium -derived hemozoin (HZ) that accumulated in TAMs inhibited IGF-1 signaling through the PI3-K and MAPK signaling pathways and thereby decreased the expression of MMP-9 in TAMs. Conclusions: Our study suggests that this novel approach of inhibiting tumor angiogenesis by Plasmodium infection is of high importance for the development of new therapies for cancer patients.

Plasmodium infection inhibits tumor angiogenesis through effects on tumor-associated macrophages in a murine implanted hepatoma model

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in China. The lack of effective treatment results in a high recurrence rate in patients who undergo radical tumor resection, and the 5-year survival rate remains low. Our previous studies demonstrated that Plasmodium infection provides a potent antitumor effect by inducing innate and adaptive immunity in a murine Lewis lung carcinoma (LLC) model. Methods: A study was conducted to investigate the inhibitory effect of Plasmodium infection on hepatocellular carcinoma in mice, and chip analysis techniques were used to find possible signal regulation mechanisms. Results: we report that Plasmodium infection efficiently inhibited tumor progression and prolonged survival in tumor-bearing mice in a murine implanted hepatoma model. The inhibition of tumor progression by Plasmodium infection is related to the suppression of tumor angiogenesis within the tumor tissue and the decreased infiltration of tumor-associated macrophages (TAMs). Further study demonstrated that TAM-produced matrix metalloprotease 9 (MMP-9) contributed to tumor angiogenesis in the tumor tissue and that the reduced expression of MMP-9 in TAMs mediated by parasite infection resulted in the suppression of tumor angiogenesis. A mechanistic study revealed that the Plasmodium-derived hemozoin (HZ) that accumulated in TAMs inhibited IGF-1 signaling through the PI3-K and MAPK signaling pathways, which led to decreased expression of MMP-9 in TAMs. Conclusions: Our study suggests that this novel method of inhibiting tumor angiogenesis by Plasmodium infection is of high importance for developing new therapies for cancer patients.