DNA-binding affinity and molecular docking studies of the PEGylated binuclear palladacycle, BTC2, an efficient metallodrug against triple-negative breast cancer

Article

作者: Mapolie, Selwyn ; van Niekerk, Annick ; Kimani, Serah ; Blanckenberg, Angelique ; Chellan, Prinessa ; Chakraborty, Suparna ; Prince, Sharon

Triple-negative breast cancer (TNBC) has a low five-year survival rate, especially if the cancer is diagnosed at a late stage and has already metastasized beyond the breast tissue. Current chemotherapeutic options for TNBC rely on traditional platinum-containing drugs like cisplatin, oxaliplatin and carboplatin. Unfortunately, these drugs are indiscriminately toxic, resulting in severe side effects and the development of drug resistance. Palladium compounds have shown to be viable alternatives to platinum complexes since they are less toxic and have displayed selectivity towards the TNBC cell lines. Here we report the design, synthesis, and characterization of a series of binuclear benzylidene palladacycles with varying phosphine bridging ligands. From this series we have identified BTC2 to be more soluble (28.38-56.77 μg/mL) and less toxic than its predecessor, AJ5, while maintaining its anticancer properties (IC₅₀ (MDA-MB-231) = 0.58 ± 0.012 μM). To complement the previous cell death pathway study of BTC2, we investigated the DNA and BSA binding properties of BTC2 through various spectroscopic and electrophoretic techniques, as well as molecular docking studies. We demonstrate that BTC2 displays multimodal DNA binding properties as both a partial intercalator and groove binder, with the latter being the predominant mode of action. BTC2 was also able to quench the fluorescence of BSA, thereby suggesting that the compound could be transported by albumin in mammalian cells. Molecular docking studies revealed that BTC2 is a major groove binder and binds preferentially to subdomain IIB of BSA. This study provides insight into the influence of the ligands on the activity of the binuclear palladacycles and provides much needed information on the mechanisms through which these complexes elicit their potent anticancer activity.

2015-02-01·Cancer Letters1区 · 医学

The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells

1区 · 医学

Article

作者: Aliwaini, Saeb ; de la Mare, Jo ; Peres, Jade ; Kröger, Wendy L ; Prince, Sharon ; Mapolie, Selwyn ; Edkins, Adrienne L ; Blanckenberg, Angelique

Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.

2013-12-01·Biochemical Pharmacology2区 · 医学

A novel binuclear palladacycle complex inhibits melanoma growth in vitro and in vivo through apoptosis and autophagy

2区 · 医学

Article

作者: Angelique Blanckenberg ; Sharon Prince ; Selwyn Mapolie ; Saeb H. Aliwaini ; Andrew J. Swarts

Malignant melanoma is an aggressive skin cancer and it is reported to be the most treatment-resistant human cancer. Here we describe the anti-tumour activity of a novel binuclear palladacycle complex (AJ-5) in vertical growth phase (ME1402) and metastatic (WM1158) melanoma cell lines. We show that compared to normal control cell lines, AJ-5 is more effective in inhibiting the proliferation of ME1402 and WM1158 melanoma cells with IC50 values of 0.19 and 0.20μM, respectively. Flow cytometry analyses showed that AJ-5 induced apoptosis (sub-G1 peak) which was confirmed by Annexin V-FITC/propidium iodide double-staining, nuclear fragmentation and an increase in the levels of PARP cleavage. Furthermore, AJ-5 was shown to induce both intrinsic and extrinsic apoptotic pathways as measured by PUMA, Bax and active caspases. Interestingly, AJ-5 treatment also simultaneously induced the formation of autophagosomes and led to an increase in the autophagy markers LC3II and Beclin1. Inhibition of autophagy reduced AJ-5 cytotoxicity suggesting that AJ-5 induced autophagy was a cell death and not cell survival mechanism. Moreover we show that AJ-5 induces the ATM-CHK2 DNA damage pathway and that its anti-tumour function is mediated by the p38 and ERK1/2 signalling pathways. Importantly, AJ-5 treatment efficiently reduced tumour growth in melanoma bearing mice and induced high levels of autophagy and apoptosis markers. Together these findings suggest that AJ-5 may be an effective chemotherapeutic drug in the treatment of melanoma, a highly aggressive and intractable cancer.

100 项与 AJ-5 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
乳腺癌	临床前	南非	University of Stellenbosch	-
黑色素瘤	临床前	南非	University of Cape Town	-
肉瘤	临床前	南非	University of Stellenbosch	-
肉瘤	临床前	南非	University of Cape Town	-