2. Academic Validation
  3. Novel bifluorescent Zn(II)-cryptolepine-cyclen complexes trigger apoptosis induced by nuclear and mitochondrial DNA damage in cisplatin-resistant lung tumor cells

Novel bifluorescent Zn(II)-cryptolepine-cyclen complexes trigger apoptosis induced by nuclear and mitochondrial DNA damage in cisplatin-resistant lung tumor cells

  • Eur J Med Chem. 2022 Aug 5;238:114418. doi: 10.1016/j.ejmech.2022.114418.
Zhen-Feng Wang 1,  Xiao-Feng Zhou 2,  Qiao-Chang Wei 3,  Qi-Pin Qin 4,  Jin-Xian Li 3,  Ming-Xiong Tan 5,  Shu-Hua Zhang 6
Affiliations

Affiliations

  • 1 College of Chemistry, Guangdong University of Petrochemical Technology, Maoming, Guangdong, 525000, PR China; Guangxi Key Laboratory of Electrochemical and Magnetochemical Functional Materials, College of Chemistry and Bioengineering, Guilin University of Technology, Guilin, 541004, PR China.
  • 2 Second Clinical Medicine College, Lanzhou University, Lanzhou, 730030, PR China.
  • 3 Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China.
  • 4 Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin, 541004, PR China. Electronic address: qpqin2018@126.com.
  • 5 Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin, 541004, PR China. Electronic address: mxtan2018@126.com.
  • 6 College of Chemistry, Guangdong University of Petrochemical Technology, Maoming, Guangdong, 525000, PR China; Guangxi Key Laboratory of Electrochemical and Magnetochemical Functional Materials, College of Chemistry and Bioengineering, Guilin University of Technology, Guilin, 541004, PR China. Electronic address: zsh720108@163.com.
PMID: 35525079 DOI: 10.1016/j.ejmech.2022.114418
Abstract

Four novel bifluorescent Zn(II)-cryptolepine-cyclen complexes, namely [Zn(BQTC)]Cl2 (Zn(BQTC)), [Zn(BQA) (Cur)Cl] (Zn(BQACur)), [Zn (TC)]Cl2 (Zn(TC)), and [Zn (AP) (Cur)Cl] (Zn(APCur)), bearing curcumin (H-Cur), cyclen (TC), 1,10-phenanthrolin-5-amine (AP), and novel cryptolepine-cyclen derivatives (BQTC and BQA) were prepared for cell nucleus- and mitochondria-specific imaging. MTT assay results indicated that Zn(BQTC) and Zn(BQACur) exhibit stronger Anticancer activity against cisplatin-resistant A549R lung tumor cells than ZnCl2, Zn(TC), Zn(APCur), H-Cur, TC, AP, BQTC, and BQA. Due to the dual fluorescence characteristic of Zn(BQTC), selective fluorescence imaging of the nucleus and mitochondria of A549R Cancer cells was conducted. Further, Zn(BQTC), obtained by the functionalization of Zn(TC) with cryptolepine derivative substituents, efficiently inhibited DNA synthesis, thus resulting in high cytotoxicity (selective for A549R lung tumor cells) accompanied by DNA impairment in nuclear and mitochondrial fractions. Additionally, Zn(BQTC) caused severe damage to the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), sequentially disrupted mitochondrial and nuclear functions, and promoted the DNA damage-induced apoptotic signaling pathway and adenosine triphosphate depletion (ATP). Thus, Zn(BQTC) can be used as an Anticancer drug by targeting mtDNA and nDNA. Most importantly, Zn(BQTC) showed higher efficacy in inhibiting Cancer growth (55.9%) in A549R tumor-bearing mice than Zn(TC) (31.2%) and cisplatin, along with a promising in vivo safety profile. These results demonstrate the applicability of the developed novel bifluorescent Zn(II)-cryptolepine-cyclen complexes as promising DNA-targeting Anticancer agents for Cancer treatment.

Keywords

Cell apoptosis; Cryptolepine–cyclen; DNA damage; Zn(II) complexes.

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