The G-quadruplex ligand, SYUIQ-FM05, targets proto-oncogene c-kit transcription and induces apoptosis in K562 cells.
BACKGROUND
N'-(7-Fluoro-5-N-methyl-10H-indolo[3,2-b]quinolin-5-ium)-N,N-dimethylpropane-1,3-diamine iodide (SYUIQ-FM05) is a semi-synthetic derivative of cryptolepine which is from Cryptolepis sanguinolenta (Lindl.) Schlechter (Periplocaeae). This ligand inhibits telomerase activity by stabilizing the G-quadruplex structure and induces growth arrest in cancer cells.


OBJECTIVE
The anticancer activity of SYUIQ-FM05 via inhibiting c-kit transcription was investigated in leukemic cells.


METHODS
The cytotoxicity of SYUIQ-FM05 in K562 cells was evaluated using a cell viability assay and flow cytometry (FCM) at 0.4, 2.0, 10.0 and 20.0 nM. Under the same concentrations of SYUIQ-FM05 or 100 nM imatinib mesylate (IM), quantitative polymerase chain reaction (Q-PCR) investigated transcription of c-kit and bcl-2, and western blotting analyzed the expression levels of c-Kit, total mitogen-activated protein kinase kinases (MEKs), phospho-MEK (p-MEK), total extracellular regulated protein kinases (ERKs), phospho-ERK (p-ERK), Bcl-2 and Bax.


RESULTS
SYUIQ-FM05 inhibited cellular growth with an IC(50) of 10.83 ± 0.05 nM in K562 cells. c-Kit transcription was suppressed 2.69-, 4.39-, 7.71- and 10.52-fold at 0.4, 2.0, 10.0 and 20.0 nM SYUIQ-FM05, respectively, which produced proportional loss of total c-Kit protein except IM. Both SYUIQ-FM05 and IM downregulated p-MEK and p-ERK. Furthermore, bcl-2 transcription was suppressed 1.58- and 1.86-fold at 10.0 and 20.0 nM SYUIQ-FM05, respectively, but 0.4 and 2.0 nM SYUIQ-FM05 had no effect. A decrease in Bcl-2 and an increase in Bax appeared in these treated cells.


CONCLUSIONS
These findings demonstrate that SYUIQ-FM05 could induce apoptosis in a leukemic cell line through inhibiting c-kit transcription, which supports the anticancer potency of SYUIQ-FM05 in c-Kit-positive leukemic cells.
Center of Preclinical Screening and Evaluation on New Drug, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
Fei-Hai
FH
Shen
Jing
J
Jin
Jia
J
Li
Yan
Y
Wang
Shao-Hua
SH
Zhu
Yu-Jing
YJ
Lu
Tian-Miao
TM
Ou
Zhi-Shu
ZS
Huang
Min
M
Huang
Zhi-Ying
ZY
Huang
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D008024:Ligands; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D011806:Quinolinium Compounds / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; C494826:BAX protein, human; D001549:Benzamides; D003959:Diamines; D004791:Enzyme Inhibitors; D007211:Indoles; D008024:Ligands; C000715470:MAS1 protein, human; C583072:N'-(7-fluoro-5-N-methyl-10H-indolo(3,2-b)quinolin-5-ium)-N,N-dimethylpropane-1,3-diamine; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011804:Quinolines; D011806:Quinolinium Compounds; D051028:bcl-2-Associated X Protein; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D019098:Telomerase