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

Aliwaini, Saeb; Peres, Jade; Kröger, Wendy L.; Blanckenberg, Angelique; Mare, Jo‐Anne de la; Edkins, Adrienne L.; Mapolie, Selwyn F.; Prince, Sharon

doi:10.1016/j.canlet.2014.11.027

Cited by 26 publications

(14 citation statements)

References 61 publications

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“…Chemical inhibition of autophagy resulted in enhancement of cell viability, suggesting that pitavastatin-DTIC-induced autophagy occurs as a cell death mechanism. In support of this, previous studies have suggested that DTIC and pitavastatin may serve a function in the induction of autophagy and specifically as a mode of cell death (15,19,38).…”

Section: Discussionsupporting

confidence: 53%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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Abstract. Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anticancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma. IntroductionMelanoma is a particularly aggressive skin cancer and its incidence is increasing faster than any other cancer worldwide (1). At present, the 10-year survival rate of patients diagnosed with advanced (stage IV) metastatic melanoma is <10% (2), which highlights the importance of early detection and treatment. The Food and Drug Administration approved the chemotherapeutic agent dacarbazine (DTIC) for the treatment of metastatic melanoma in 1975, and it remains the only licensed chemotherapeutic agent in use today (1). DTIC is a methylating agent which causes DNA damage, cell cycle arrest and apoptosis. Despite this, only 2% of all patients with metastatic melanoma receiving this treatment demonstrate a significant response and only 11.2% demonstrate a partial response (3). Resistance to DTIC has been associated with the upregulation of pro-survival signals and anti-apoptotic molecules in cancer cells. Despite its moderate effects, DTIC continues to be the standard treatment for metastatic melanoma as no other chemotherapeutic treatment has been demonstrated to have a significantly increased chance of survival when compared with DTIC (4,5). Provided the limited efficacy of the current metastatic melanoma chemotherapies in addition to the increasing incidence of melanoma cases, there appears to be a need for the development of more effective treatment strategies.Statins are a group of drugs commonly used for the reduction of cholesterol levels (6). They work by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a critical enzyme in the mevalonate pathway, which is responsible for cholesterol synthesis (6,7). In addition, statins have been de...

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Section: Discussionsupporting

confidence: 53%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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“…For example, cisplatin induced autophagy was shown to play a pro-survival role in esophageal cancer cells ( Liu et al, 2011 ). On the other hand, autophagy induced by the palladacycle AJ-5 was shown to play a pro-death role in melanoma and breast cancer cells ( Aliwaini et al, 2013 , Aliwaini et al, 2015 ). Therefore to determine whether KB2 induced autophagy is a pro-death or pro-survival mechanism, we measured the impact of blocking autophagy with bafilomycin-A1 on the effect of KB2 on cell viability.…”

Section: Resultsmentioning

confidence: 99%

Galenia africana plant extract exhibits cytotoxicity in breast cancer cells by inducing multiple programmed cell death pathways

Mohamed

Chakraborty

ArulJothi

et al. 2020

Saudi Pharmaceutical Journal

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“…Active BAX disrupts the mitochondrial membrane integrity and induces the cytochrome c release from mitochondria into the cytosol. Cytoplasmic cytochrome c and active caspase-9 are then involved in the apoptosome formation and caspase-3 activation (29). However, cytochrome c release does not happen when the anti-apoptotic protein BCL2 is present.…”

Section: Discussionmentioning

confidence: 99%

Novel imidazo[1,2‑a]pyridine inhibits AKT/mTOR pathway and induces cell cycle arrest and apoptosis in melanoma and cervical cancer cells

et al. 2019

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The present study aimed to investigate the anti-cancer activity of imidazo[1,2-a]pyridine 5–7 in the A375 and WM115 melanoma and HeLa cervical cancer cell lines. The viability of cancer cells was analyzed by the MTT assay. Apoptosis was quantified by flow cytometry following staining of the cells with AnnexinV/propidium iodide (PI). The cell cycle was evaluated by flow cytometry after staining of cells with PI. The three compounds inhibited the proliferation of all cells for half maximal inhibitory concentration ranging from 9.7 to 44.6 µM following 48-h treatment. In addition, all cancer cells were more sensitive to compound 6 compared with the other compounds. Treatment with compound 6 induced G 2 /M cell cycle arrest and a significant increased level of intrinsic apoptosis in all tested cells. Furthermore, compound 6 reduced the levels of phospho (p)-protein kinase B and p-mechanistic target of rapamycin, and increased levels of the cell cycle inhibitors p53 and p21 and of the apoptosis-associated proteins BCL2 associated X protein and active caspase-9. Silencing p53 in A375 melanoma cells reduced compound 6-induced apoptosis, which suggested that compound 6 may induce p53-partially mediated apoptosis. These results demonstrated that imidazo[1,2-a]pyridines 5–7 are potential effective compounds in the treatment of melanoma and cervical cancers.

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

Cited by 26 publications

References 61 publications

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Galenia africana plant extract exhibits cytotoxicity in breast cancer cells by inducing multiple programmed cell death pathways

Novel imidazo[1,2‑a]pyridine inhibits AKT/mTOR pathway and induces cell cycle arrest and apoptosis in melanoma and cervical cancer cells

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