ABSTRACT
The introduction of selenium-containing functional groups into steroids to study the biological activities of related derivatives is rarely reported in the literature. In the present study, using cholesterol as raw material, four cholesterol-3-selenocyanoates and eight B-norcholesterol selenocyanate derivatives were synthesized, respectively. The structures of the compounds were characterized by NMR and MS. The results of the in vitro antiproliferative activity test showed that the cholesterol-3-selenocyanoate derivatives did not exhibit obvious inhibitory on the tested tumor cell lines. However, the B-norcholesterol selenocyanate derivatives obtained by structural modification of cholesterol showed good inhibitory activity against the proliferation of tumor cell. Among them, compounds 9b-c, 9f and 12 showed similar inhibitory activity against tested tumor cells as positive control 2-methoxyestradiol, and better than Abiraterone. At the same time, these B-norcholesterol selenocyanate derivatives displayed a strong selective inhibitory against Sk-Ov-3 cell line. Except for compound 9g, the IC50 value of all B-norcholesterol selenocyanate compounds against Sk-Ov-3 cells was less than 10 µM, and compound 9d was 3.4 µM. In addition, Annexin V-FITC/PI double staining was used to analyze the cell death mechanism. The results showed that compound 9c could induce Sk-Ov-3 cells to enter programmed apoptosis in a dose-dependent manner. Furthermore, the in vivo antitumor experiments of compound 9f against zebrafish xenograft tumor showed that 9f displayed obvious inhibitory effect on the growth of human cervical cancer (HeLa) xenograft tumor in zebrafish. Our results provide new thinking for the study of such compounds as new antitumor drugs.
Subject(s)
Antineoplastic Agents , Cholesterol , Animals , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis , Cell Line, Tumor , Cell Proliferation , Cholesterol/chemistry , Cholesterol/pharmacology , Drug Screening Assays, Antitumor , Molecular Structure , Structure-Activity Relationship , Zebrafish/metabolism , Cyanates/chemistry , Cyanates/pharmacology , Selenium Compounds/chemistry , Selenium Compounds/pharmacologyABSTRACT
Restructuring of cyclophosphamide (CPA) is a promising method for the development of antineoplastic therapy. This study investigated the inhibitory effects of a derivative of CPA, SLXM-2, on hepatocarcinoma 22 (H22) transplanted into ICR mice as well as its effects on the survival time of mice transplanted with the ascitic fluid-type H22. We found that SLXM-2 inhibited tumor growth and prolonged survival time. Moreover, the compound had little effect in vivo on leukocytes and body weight and a higher lethal dose 50 than CPA. The cell cycle analysis by flow cytometry revealed that SLXM-2 arrested tumor cells in both the S and G2 phases, and the arrest in the G2 phase increased in a dose-dependent manner. Western blotting and reverse transcription-PCR experiments indicated that the observed G2 arrest was associated with an increase of cyclin B1, whereas cell division cycle protein 2 (Cdc2) remained constant. The results, however, showed an accumulation of tyrosine 15 phosphorylated Cdc2 and a reduction of threonine 161 phosphorylated Cdc2. In addition, SLXM-2 led to a decrease in cyclin-dependent kinase 7 and Cdc25c kinase, which participated in inhibiting the G2/M transition. Our data identified two upstream targets leading to the inactivity of the cyclin B1/Cdc2 complex, which explained the arrest in the G2/M phase following SLXM-2 treatment. These results demonstrated the antitumor activity of SLXM-2 and its potential use as an antineoplastic drug.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Cyclophosphamide/analogs & derivatives , Cyclophosphamide/therapeutic use , Liver Neoplasms, Experimental/drug therapy , Piperazines/therapeutic use , Animals , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/therapeutic use , Blotting, Western , CDC2-CDC28 Kinases/genetics , CDC2-CDC28 Kinases/metabolism , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin B/genetics , Cyclin B/metabolism , Cyclin B1 , Cyclophosphamide/administration & dosage , Cyclophosphamide/chemistry , Dose-Response Relationship, Drug , Flow Cytometry , G2 Phase/drug effects , Gene Expression/drug effects , Injections, Intraperitoneal , Leukocyte Count , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Inbred ICR , Molecular Structure , Piperazines/administration & dosage , Piperazines/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , S Phase/drug effects , Weight Loss/drug effectsABSTRACT
OBJECTIVE: To explore nm23 gene mRNA expression and its clinical significance in acute leukemias (AML). METHODS: The levels of nm23-H1 and nm23-H2 transcripts in 22 patients with acute myeloid leukemia (AML), 9 AML in complete remission (AML-CR), 12 acute lymphoblastic leukemia (ALL) and 4 chronic myeloid leukemia in chronic phase (CML-CP) were assayed by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: The expression of nm23-H1 in AL especially in AML-M4 and AML-M5 was significantly higher than that in normal blood cells. An analysis of correlation between nm23 expression and clinicopathological parameters showed that increased nm23-H1 mRNA levels were associated with some poor-prognostic factors such as extramedullary infiltration, high white blood cell count (WBC), high lactate dehydrogenase (LDH) activity and high CD(7) expression, while inversely correlated with t(8; 21) and t(15; 17) which had a good-prognostic effect. The expression of nm23-H1 in AML patients in CR was significantly decreased compared with those untreated. CONCLUSION: nm23-H1 was overexpressed in AL, especially in AML-M4 and AML-M5. High expression of nm23-H1 may be a poor prognostic factor.
