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Abstract
Huachansu (HCS), a hot water extract of the skin glands of Bufo gargarizans (B. melanostictus), has been used extensively in the treatment of various solid tumors in Asia, particularly in China. However, its effect on the growth of malignancies of hematopoietic origin, particularly lymphomas, is limited. Here we investigated the antiproliferative effect and molecular mechanisms of HCS using non-Hodgkin’s lymphoma (NHL) Raji, Ramos, and Namalwa cells and the mantle cell lymphoma cells SP53. HCS inhibited proliferation in these cell lines with an IC50 ranging from 3.1 to 25 μl/ml. At a concentration of 25 μl/ml, HCS triggered a sub-G1 arrest in Ramos cells and induced early to late apoptotic cell death. Cleaved caspase-3 was formed in a concentration-dependent manner in Ramos cells following treatment with HCS for 24 h. Intriguingly, when the Ramos cells were treated with the caspase inhibitor ZDEVD, the apoptotic activity of HCS was partially blocked. Furthermore, HCS also blocked the expression of survivin and pRB proteins in a concentration-dependent manner in Ramos cells. Mechanistically, HCS downregulated both the MAPK gene and proteins in Ramos cells. Collectively, our data suggest that HCS is effective in inducing cell death and apoptosis, in part, by activating caspase-3 activity and suppressing MAP kinase in NHL cells.
Highlights
Non-Hodgkin's lymphomas (NHLs) are common hematologic malignancies representing ~5.3% of all cancers in the United States and >50% of all blood cancers [1]
A comparable level of antiproliferative effect, IC50 of ~1.5 μl/ml, was achieved when mantle cell lymphoma SP53 cells were treated with HCS (Fig. 1A)
In contrast to the lymphoma cells, HCS did not affect the proliferation of human peripheral blood mononuclear cell (PBMC) (Fig. 1A)
Summary
Non-Hodgkin's lymphomas (NHLs) are common hematologic malignancies representing ~5.3% of all cancers in the United States and >50% of all blood cancers [1]. B-cell lymphomas are the most common types of NHLs. Despite the considerable research progress on lymphomas, as well as the improved treatment regimens, the survival statistics remain poor, especially for the aggressive forms of NHLs. Currently, combination therapy is the preferred treatment modality for lymphoma, albeit with significant adverse side effects, for the more aggressive types, such as Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). The majority of patients with BL respond poorly to the CHOP treatment [2]. Many patients with MCL have a poor response to CHOP, have high rates of relapse, with a median survival rate of 3-5 years [3]. Finding drugs that target BL and MCL while sparing normal cells is a major focus of current research. Because treatment failure depends on a complex interplay of factors including tumor biology, pharmacokinetics and pharmacogenomics [4,5], the use of natural products, such as Huachansu (HCS), comprising many bioactive components [6] may prove to be more efficacious than a single agent or single agent combinations
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