Design, synthesis and antineoplastic activity of novel hybrids of podophyllotoxin and indirubin against human leukaemia cancer cells as multifunctional anti-MDR agents

Wang, Jing; Long, Li; Chen, Yongzheng; Xu, Yingshu; Zhang, Lei

doi:10.1016/j.bmcl.2018.04.019

Cited by 30 publications

(11 citation statements)

References 55 publications

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“…In terms of molecular mechanisms, the results showed an upregulation of the expression of the cell cycle-related protein CDK1 and downregulation of the expression of cyclin B1, a protein required for mitotic initiation. Wang J. et al (2018) synthesized PTOX-indirubin hybrids Compound 43 ( Figure 10 ), which resulted in apoptosis and cell cycle arrest in human leukemia cells (K562/VCR). Meanwhile, PTOX-indirubin hybrids elicited the accumulation of intracellular ROS, regulated JNK and AKT signaling, and downregulated the expression levels of P-gp and MRP1 proteins.…”

Section: Mechanism Of Ptox Derivatives As An Anticancer Drugmentioning

confidence: 99%

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

Fan

Zhu

Xian

et al. 2021

Front. Cell Dev. Biol.

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Podophyllotoxin (PTOX) is a biologically active compound derived from the podophyllum plant, and both it and its derivatives possess excellent antitumor activity. The PTOX derivatives etoposide (VP-16) and teniposide (VM-26) have been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment, but are far from perfect. Hence, numerous PTOX derivatives have been developed to address the major limitations of PTOX, such as systemic toxicity, drug resistance, and low bioavailability. Regarding their anticancer mechanism, extensive studies have revealed that PTOX derivatives can induce cell cycle G2/M arrest and DNA/RNA breaks by targeting tubulin and topoisomerase II, respectively. However, few studies are dedicated to exploring the interactions between PTOX derivatives and downstream cancer-related signaling pathways, which is reasonably important for gaining insight into the role of PTOX. This review provides a comprehensive analysis of the role of PTOX derivatives in the biological behavior of tumors and potential molecular signaling pathways, aiming to help researchers design and develop better PTOX derivatives.

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Section: Mechanism Of Ptox Derivatives As An Anticancer Drugmentioning

confidence: 99%

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

Fan

Zhu

Xian

et al. 2021

Front. Cell Dev. Biol.

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“… 47 Our group reported that hybrid of podophyllotoxin and indirubin, 6, could induce K562/VCR cells autophagy. 24 However, no paper had demonstrated that podophyllotoxin or its derivative could induce autophagy in resistant K562/ADR cell line. In this study, we were eager to determine whether molecule S1 influenced autophagy in K562/ADR cells.…”

Section: Resultsmentioning

confidence: 99%

“…It was observed that 6 induced apoptosis and cell cycle arrest, caused the accumulation of ROS, regulated AKT and JNK signaling, and suppressed the expression levels of P-gp and MRP1 proteins. 24 …”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel nitric oxide-donating podophyllotoxin derivatives as potential antiproliferative agents against multi-drug resistant leukemia cells

et al. 2018

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Multidrug resistance remains a major obstacle for the effective treatment of carcinoma. To find new drugs for the chemotherapy of drug-resistant leukemia, in this study, two novel nitric oxide-donating podophyllotoxin derivatives were synthesized and preliminarily evaluated in vitro. Biological evaluation indicated that the more active molecule, S1, enhanced the intracellular NO level and significantly inhibited the proliferation of drug-resistant K562/VCR and K562/ADR cells with IC 50 values of 0.008 AE 0.001 and 0.007 AE 0.001 mM, respectively, which were similar to that of sensitive K562 cells.Furthermore, it was observed that S1 blocked the G2 phase of the K562/ADR cell cycle by disruption of the microtubule organization and inhibition of CDK1 and CDK2 expression. Meanwhile, S1 induced apoptosis of K562/ADR cells via mitochondrial depolarization and activation of caspase-3. In addition, S1 suppressed the P-gp expression, induced autophagy by regulation of Beclin1 and LC3-II, and inhibited the mTOR and STAT3 signaling in K562/ADR cells. Overall, S1 may be a promising candidate against drug-resistant leukemia.

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“…The podophyllotoxin-indirubin hybrid termed Da-1 suppresses the proliferation of leukemia cells and induces autophagy ( 26 ). The autophagy-inducing effect of podophyllotoxin has also been demonstrated in HCC cells ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Podofilox suppresses gastric cancer cell proliferation by regulating cell cycle arrest and the c‑Myc/ATG10 axis

Liu

Duo

et al. 2021

Exp Ther Med

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Gastric cancer (GC) is a malignancy for which effective therapeutic drugs are limited. Podofilox exhibits antitumor effects in various types of cancer; however, whether it may inhibit GC growth remains unknown. The aim of the present study was to investigate the role of podofilox in GC. Cell Counting Kit-8, colony formation and cell cycle assays were used to detect the role of podofilox on cellular proliferation and the cell cycle, respectively. A microarray was used to detect the transcriptional changes induced by podofilox in GC cells. The results of the present study demonstrated that podofilox inhibited GC cell proliferation and colony formation. The half maximal inhibitory concentration of podofilox in AGS and HGC-27 cells was 2.327 and 1.981 nM, respectively. In addition, treatment with podofilox induced G 0 /G 1 cell cycle arrest. Molecular analysis based on microarray data demonstrated that podofilox altered the expression levels of genes involved in the cell cycle, c-Myc and p53 signaling. Autophagy-related 10 (ATG10), which was highly expressed in GC tissues, was also downregulated by podofilox, as demonstrated by the results of the microarray analysis and immunoblotting. To determine the involvement of ATG10 in GC, ATG10 was knocked down in GC cells by small interfering RNA, which suppressed the proliferation and colony formation of GC cells compared with those observed in the control-transfected cells. Taken together, the results of the present study suggested that podofilox may inhibit GC cell proliferation by preventing the cell cycle progression and regulating the c-Myc/ATG10 signaling pathway.

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Design, synthesis and antineoplastic activity of novel hybrids of podophyllotoxin and indirubin against human leukaemia cancer cells as multifunctional anti-MDR agents

Cited by 30 publications

References 55 publications

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

Design, synthesis and biological evaluation of novel nitric oxide-donating podophyllotoxin derivatives as potential antiproliferative agents against multi-drug resistant leukemia cells

Podofilox suppresses gastric cancer cell proliferation by regulating cell cycle arrest and the c‑Myc/ATG10 axis

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