Abstract
Lp16-PSP (Latcripin 16-Perchloric acid Soluble Protein) from Lentinula edodes strain C91-3 has been reported previously in our laboratory to have selective cytotoxic activity against a panel of human cell lines. Herein, we have used several parameters in order to characterize the Lp16-PSP-induced cell death using human acute promyeloid leukemia (HL-60) as a model cancer. The results of phase contrast microscopy, nuclear examination, DNA fragmentation detection and flow cytometry revealed that high doses of Lp16-PSP resulted in the induction of apoptosis in HL-60 cells. The colorimetric assay showed the activation of caspase-8, -9, and -3 cascade highlighting the involvement of Fas/FasL-related pathway. Whereas, Western blot revealed the cleavage of caspase-3, increased expression of Bax, the release of cytochrome c and decreased expression of Bcl-2 in a dose-dependent manner, suggesting the intrinsic pathway might be involved in Lp16-PSP-induced apoptosis as well. Low doses of Lp16-PSP resulted in the anchorage-independent growth inhibition, induction of G1 phase arrest, accompanied by the increased expression of p21WAF1/CIP1, along with the decreased expression of cyclin D, E, and cdk6. In addition, Lp16-PSP resulted in constitutive translocation inhibition of transcription factor nuclear factor kappa B (NF-κB) into the nucleus by decreasing the phosphorylation of IκBα. All these findings suggested Lp16-PSP as a potential agent against acute promyeloid leukemia; however, further investigations are ultimately needed.
Highlights
In the United States, approximately every three minutes a person is diagnosed with hematological cancer [1]
Acute promyeloid leukemia (APL) is the clear subtype of acute myeloid leukemia (AML), which is caused by leukocyte differentiation arrest at the promyelocyte stage and was considered as fatal before the discovery of all-trans retinoic acid (ATRA), the derivative of vitamin A [4]
Our findings demonstrated that the effect and molecular mechanism behind the action of Lp16-PSP are associated with the inhibition of the constitutive translocation of NF-κB into the nucleus by decreasing the phosphorylation of IκBα in human acute premyeloid leukemia (HL-60 cells)
Summary
In the United States, approximately every three minutes a person is diagnosed with hematological cancer [1]. Acute promyeloid leukemia (APL) is the clear subtype of AML, which is caused by leukocyte differentiation arrest at the promyelocyte stage and was considered as fatal before the discovery of all-trans retinoic acid (ATRA), the derivative of vitamin A [4]. APL patients were defined as low-risk for relapse (WBC ≤ 10,000/μL and platelet count ≈ 440,000/μL), intermediate-risk (WBC ≤ 10,000/μL and platelet count ≤ 40,000), and high-risk (WBC ≈ 410,000/μL) on the basis of cell count [5]. As far as therapy for newly-diagnosed APL patients is concerned, in the last two decades, it has excogitated from an all-trans retinoic acid (ATRA) + chemotherapy to the arsenic trioxide (ATO) addition, followed by the chemotherapy omission in low-risk patients [6]
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