Stabilization of c-myc G-Quadruplex DNA, inhibition of telomerase activity, disruption of mitochondrial functions and tumor cell apoptosis by platinum(II) complex with 9-amino-oxoisoaporphine.
[Pd(L)(DMSO)Cl2] (1) and [Pt(L)(DMSO)Cl2] (2) with 9-amino-oxoisoaporphine (L), were synthesized and characterized. 1 and 2 are more selectively cytotoxic to Hep-G2 cells versus normal liver cells (HL-7702). Various experiments showed that 2 acted as telomerase inhibitors targeting G4-DNA and triggered cell apoptosis by interacting with c-myc G4-DNA. Furthermore, 2 significantly induced cell cycle arrest at both G2/M and S phase, which leading to the down-regulation of cdc25 A, cyclin D, cyclin B, cyclin A and CDK2 and the up-regulation of p53, p27, p21,chk1 and chk2. In addition, 2 also caused mitochondrial dysfunction. Taken together, we found that 2 exerted its cytotoxic activity mainly via inhibiting telomerase by interaction with c-myc G4-DNA and disruption of mitochondrial function.
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Jiao-Lan
JL
Qin
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Qi-Pin
QP
Qin
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Zu-Zhuang
ZZ
Wei
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Yan-Cheng
YC
Yu
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Ting
T
Meng
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Chen-Xuan
CX
Wu
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Yue-Lan
YL
Liang
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China.
Hong
H
Liang
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China. Electronic address: chenzf@gxnu.edu.cn.
Zhen-Feng
ZF
Chen
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001060:Aporphines / Q000737:chemistry; D001692:Biological Transport; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D001060:Aporphines; D009942:Organometallic Compounds; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; C081279:aporphine; D010984:Platinum; D004247:DNA; D019098:Telomerase
9-Amino-oxoisoaporphine; Antitumor activity; Cells apoptosis; Palladium(II) and platinum(II) complexes; Telomerase