Selective permeabilization of cervical cancer cells to an ionic DNA‐binding cytotoxin by activation of P2Y receptors

Bukhari, Maurish; Deng, Han; Jones, Noelle; Towne, Zachary; Woodworth, Craig D.; Samways, Damien S. K.

doi:10.1016/j.febslet.2015.04.044

Cited by 8 publications

(10 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our group has recently reported the growth inhibition induced byATP at 32 μM (log[ATP]=-4.5) and higher doses on prostate cancer cell lines (29). In addition, ATP at a very high dose in the range of milli molar was reported to induce cytotoxicity and apoptosis in many cancer types such as hepatoma, adenocarcinoma, and cervical cancer cells (24,(30)(31)(32)(33). On the other hand, some studies have showed that 10 μM ATP and lower doses stimulated growth and motility of ovarian cancer (34), hepatoma (19), breast cancer (23), lung cancer (25), and prostate cancer cells (20,35).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

Lertsuwan

Ruchirawat

2017

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

Lertsuwan

Ruchirawat

2017

View full text Add to dashboard Cite

show abstract

“…Stimulation of P2Y 1 R on HeLa cells triggered epidermal growth factor receptor mitogen signalling and P2Y 1 antagonists reduced proliferation. Permeabilisation of cervical cancer cells to a cytotoxin is activated by P2YR ( Bukhari et al, 2015 ). P2Y 6 R activation induces HeLa cell migration ( Gendaszewska-Darmach and Szustak, 2016 ).…”

Section: Diseases Of the Reproductive Systemmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

View full text Add to dashboard Cite

Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

show abstract

“…In a previous study, we demonstrated that extracellular ATP stimulates the uptake and accumulation of H33258 into cervical cancer cells in a concentration-dependent manner that does not require the hydrolysis of ATP ( 1 ). We began by reproducing this key finding, using CXT2 cervical cancer cells cultured on glass coverslips mounted into a bath on the stage of a Nikon TE200 inverted microscope and perfused with extracellular solution.…”

Section: Resultsmentioning

confidence: 99%

“…1D and E). Investigating the role of SOCE in the ATP-evoked H33258 uptake at higher [Ca 2+ ]i is complicated by a concentration-dependent suppression of ATP-evoked H33258 uptake by [Ca 2+ ]o [1]. The reason for this is unclear, but appears to be specific to the ATP-evoked uptake, as direct activation of KCa3.1 with SKA 31 still evoked substantial H3358 uptake in physiological [Ca 2+ ]o (Supporting information Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous article, we demonstrated that application of extracellular ATP stimulated the rapid uptake and accumulation of a small molecule DNA-binding cationic dye, Hoechst 33258 (H33258), into cultured cervical cancer cells in a manner dependent on both the ATP and H33258 concentrations ( 1 ). Moreover, analysis of a wide spectrum of cervical epithelial cell cultures derived from both normal and cancerous tissue revealed that the uptake was preferentially observed in cancerous cells.…”

mentioning

confidence: 99%

See 1 more Smart Citation

KCa3.1-dependent uptake of the cytotoxic DNA-binding dye Hoechst 33258 into cancerous but not healthy cervical cells

Bukhari

Deng

Sipes

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The poor and nonselective penetration of current chemotherapeutics across the plasma membranes of cancer cells, which is necessary for the targeted disruption of the intracellular machinery, remains a major pharmaceutical challenge. In several cell types, including mast cells and macrophages, exposure to extracellular ATP is known to stimulate passive entry of large and otherwise membrane impermeable cationic dyes, which is usually attributed to conduction through ionotropic P2X receptors. Here, we report that elevations in cytosolic Ca2+ stimulate the rapid uptake and nuclear accumulation of a DNA-binding fluorescent cation, Hoechst 33258 (H33258), in cervical cancer cells. The H33258 uptake was dependent on activation of intermediate conductance Ca2+-activated K+ channels (KCa3.1), and direct stimulation of the channel with the activators SKA 31 and DCEBIO was sufficient to induce cellular uptake of H33258 directly. In contrast to the results from cancerous cervical cells, KCa3.1-dependent H33258 uptake was rarely observed in epithelial cells derived from the ectocervix and transformation zone of healthy cervical tissue. Furthermore, whole-cell patch clamp experiments and assessment of membrane potential using the slow voltage-sensitive dye DiSBAC2(3) revealed a significant difference in functional KCa3.1 activity between cancerous and healthy cervical epithelial cells, which correlated strongly with the incidence of KCa3.1-dependent H33258 uptake. Finally, we show that activation of KCa3.1 channels caused a modest but significant sensitization of cancer cells to the growth suppressant effects of H33258, lending plausibility to the idea of using KCa3.1 channel activators to enhance cell penetration of small cationic toxins into cancer cells expressing these channels.

show abstract

Selective permeabilization of cervical cancer cells to an ionic DNA‐binding cytotoxin by activation of P2Y receptors

Cited by 8 publications

References 42 publications

Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

Purinergic Signalling: Therapeutic Developments

KCa3.1-dependent uptake of the cytotoxic DNA-binding dye Hoechst 33258 into cancerous but not healthy cervical cells

Contact Info

Product

Resources

About