Antitumor potential of a novel camptothecin derivative, ZBH-ZM-06

Abstract

Camptothecin (CPT) is a cytotoxic quinoline alkaloid that is used clinically as an anticancer drug. However, the clinical application of CPT is limited due to its low solubility as well as serious and unfathomable side-effects. In the present study, we created a novel 10-hydroxy CPT prodrug, ZBH-ZM‑06. Its cellular cytotoxic activity was analyzed in terms of cellular viability, acetylcholinesterase (AchE) inhibition, DNA relaxation, cellular cycling and apoptosis properties. Our results showed that the AchE inhibition rate of 10 µmol/l ZBH-ZM-06 was 12.5%, compared to 96.5% for carbonyl-oxycamptothecin (CPT-11). In a chemical stability assay, only 4.9% of ZBH-ZM-06 remained after 4 h at pH 7.4. In addition, 10 µmol/l ZBH-ZM-06 significantly inhibited the tumor cell viability of nine tumor cell lines, compared to CPT-11 and the CPT active ingredient, 7-ethyl-10-hydroxy-camptothecin (SN38) (p<0.01-0.05). In the apoptosis assay, ZBH-ZM-06 increased the ratio of annexin V+/propidium iodide (PI)-/+ cells by flow cytometric analysis (p<0.05). Moreover, ZBH-ZM-06 activated caspase-3 and poly(ADP-ribose)polymerase (PARP) expression by immunoblotting. Furthermore, ZBH-ZM-06 induced a greater G2/M phase arrest ratio, compared to CPT-11 and SN38. These results indicated that ZBH-ZM-06 had higher antitumor activity than CPT-11 and SN38, which was shown by its: i) release of the effective ingredient; ii) growth inhibition of a broad spectrum of tumor cells; iii) inhibition of DNA topoisomerase (Topo-1); and iv) promotion of apoptosis through an intrinsic signaling pathway. Thus, ZBH-ZM-06 may be applied in the preclinic study for cancer treatment.

A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle

“…The DNA relaxation assay unexpectedly showed that the inhibition of ZBH-01 on TOP1 was signi cantly lower than CPT-11 and SN38. This was inconsistent with our previous reports [9,11]. Then, we con rmed this result using NGS and qRT-PCR.…”

“…2). This result was contradictory to our previous reports [9,11], which might indicate the heterogeneity and complexity of ZBH-01 mechanisms. Nevertheless, after treatment with 50 nmol/L ZBH-01 for 24 h, LS174T cells presented decreased protein levels of TOP1 (Fig.…”

“…In the last ten years, our research group designed and synthesized a series of novel irinotecan derivatives characterized by higher antitumor activity for tumor cells and lower toxicity for epithelial cells compared to CPT-11 [9][10][11]. However, the molecular mechanisms of these new derivatives still need to be precisely elucidated.…”

Tetrandrine: a review of its anticancer potentials, clinical settings, pharmacokinetics and drug delivery systems

“…[ 13,24 ] Additionally, natural products targeting the molecular signalling pathways of cell invasion, metastasis, division, apoptosis and autophagy are considered the foundation for the treatment of multiple cancers through the respective signalling pathways. [ 25 ] Phytochemicals, like vincristine, [ 26,27 ] curcumin, [ 28 ] taxol, [ 29 ] plumbagin, [ 30 ] luteolin, [ 31 ] camptothecin [ 32 ] and podophyllotoxin, [ 33 ] are some of the leading and approved anticancer drugs from natural plants and TCM. Importantly, the rapid development of new technologies and novel analysis methods, such as combinatorial syntheses, nanoparticle drug delivery systems and high‐throughput screenings, has brought a fresh perspective to the discovery and the design of new chemical constituents from natural sources.…”

Ethyl Acetate Extract of Asclepias curassavica Induced Apoptosis in Human Cancer Cells via Activating p38 and JNK MAPK Signaling Pathways

“…Many chemotherapeutic agents have been thought as modulators in apoptosis-inducing signal transduction pathways, which contain the mitochondrial pathway, external death receptor pathway, and endoplasmic reticulum pathway [20]. Among them, Fas and FasL are mainly involved in the external death receptor pathway [21, 22]. Depending on the binding of Fas-associated protein to the death domain, caspase family cascade reactions are induced, which give rise to the degradation of DNA fragments and apoptosis [23].…”