A group of scientists from The Scripps Research Institute (Fl, USA) has reported two new drug candidates for the treatment of pain, drug addiction and other disorders.
The study, led by Laura Bohn, identified small-molecule agonists of the kappa opioid receptor (KOR), termed ‘biased agonists’. The KOR, which is expressed in the CNS, modulates stress response, pain perception and affective reward states. The receptor has therefore been a therapeutic target in drug development for pain, drug addiction and depression treatment. Molecules that activate KOR are associated with positive therapeutic effect. However, activation of the receptor can lead to b-arrestin 2 recruitment, which is linked with the onset of depression. Agonists that activate the KOR without also recruiting b-arrestin 2 are seen as attractive as they limit potential side effects.
The team demonstrated that unlike other KOR agonists, the biased agonists activate downstream signaling pathways preferentially. The researchers concede further research will be needed to establish whether this unique property will be therapeutically beneficial, as explained by Bohn: “Regardless, we now have important new tools to begin to answer the questions of what signaling pathways are important in producing and regulating specific physiologies in a manner that may lead to a greater understanding of how we should attempt to treat human diseases, such as drug addiction relapse, pain and depression.”
Bohn described the further work the team is undertaking, “Our future studies will involve further compound development, in which we seek to enrich the scaffolds to introduce more nuances in directing receptor signaling. Simultaneously, we will be using these tools to elucidate KOR function in the endogenous setting.”
– Written by Jessica Thorne
Sources: TSRI scientists develop promising drug candidates for pain, addiction: www.scripps.edu/news/press/2014/20140113bohn.html; Zhou L, Lovell KM, Frankowski KJ et al. Development of functionally selective, small molecule agonists at kappa opioid receptors. J. Biol. Chem. 288(51), 36703–36716 (2013).
Researchers from the University of Copenhagen (Copenhagen, Denmark), in partnership with the Nano-Science Center (Copenhagen, Denmark) and the Insitut Laue-Langevin (Grenoble, France) have demonstrated that reservoirs of pharmaceuticals could be manufactured to bind specifically to diseased tissue, such as cancer cells, for the slow, concentrated delivery of therapeutic drugs.
The attachment of reservoirs of therapeutic drugs to cell membranes for slow diffusion and continuous delivery inside the cells is a significant goal in drug R&D. A group of self-assembling liquid crystalline particles, specifically phospholipids and dendrimers, have been identified as promising candidates for the transport of such drug reservoirs due to their capacity to carry large quantities of drug molecules for prolonged diffusion, in addition to their ability to bind to cellular membranes.
To provide an insight into drug formulations containing such particles, the team, led by Marité Cárdenas from the University of Copenhagen, conducted a study towards understanding how self-assembled liquid crystalline aggregates of dendrimers and phospholipids interact with cellular membranes.
The team carried out neutron reflectometry measurements on supported bilayers of varying charge and on hydrophilic silica surfaces to analyze the interaction of the liquid crystalline particles with a model cellular membrane when exposed to changes in gravity and electrostatics. Translocation of the macromolecule across the membrane and adsorption of the lamellar aggregates was discovered to only occur when the membrane was located above the bulk liquid and had sufficient negative charge.
The sensitivity of the membrane–particle interaction to small changes in charge suggests that simple adjustments to the proportion of charged lipids and macromolecules could optimize this process. The team also envisaged that, in the future, this characteristic could provide a mechanism to focus the treatment at targeted cells such as those affected by cancer, which are thought to have a more negative charge density than healthy cells. “Cancerous cells have an imbalance that gives them a different molecular composition and overall different physical properties to normal healthy cells”, explained Cardenas. “While all cells are negative, cancerous cells tend to be more negatively charged than healthy ones due to a different composition of fatty molecules on their surface. This is a property that we believe could be exploited in future research into delivery mechanisms involving the attachment of lamellar liquid crystalline particles.”
– Written by Hannah Coaker
Sources: Campbell RA, Watkins EB, Jagalski V, Åkesson-Runnsjö A, Cárdenas M. Key factors regulating the mass delivery of macromolecules to model cell membranes: gravity and electrostatics. ACS Macro Lett. 3, 121–125 (2014); World’s tiniest drug cabinets could be attached to cancerous cells for long term treatment: http://chem.ku.dk/om/news/newslist/marit
A global group of researchers has discovered that perphenazine, an antipsychotic medication, has anticancer effects against T-cell acute lymphoblastic leukemia (T-ALL), which due to the aggressive nature of the cancer causes fatality in 20% of children and 50% of adults who are diagnosed with the disease.
The team screened 4800 compounds in a T-ALL zebrafish model, as explained by Thomas Look, one of the lead researchers on the study from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center (MA, USA): “We wanted to see if there were drugs or known bioactive molecules that are active against T-ALL that had not been tested yet.” Look continued, “There may be drugs available for other indications that could be readily repurposed if we can show activity.”
The study demonstrated that the drug perphenazine, which has not been used for 50 years and blocks dopamine receptors, is a promising candidate for future T-ALL treatment, due to its ability to induce apoptosis. The team confirmed their findings in several different models, including human T-ALL cells.
The team identified PP2A, a tumor suppressor gene, as the target of perphenazine, using quantitative mass spectrometry. The study demonstrated that perphenazine is able to reactivate PP2A activity, which is suppressed in tumor cells. Look’s colleague on the study, Alejandro Gutierrez, commented, “We rarely find potential drug molecules that activate an enzyme. Most new drugs deactivate some protein or signal that the cancer cell requires to survive. But, here, perphenazine is restoring the activity of PP2A in the T-ALL cell.”
Look explained the potential of targeting PP2A in range of different cancers, “The proteins that PP2A suppresses, such as Myc and Akt, are involved in many tumors. We are optimistic that PP2A activators will have quite broad activity against different kinds of cancer, and we‘re anxious to study the pathway in other malignancies as well.”
– Written by Jessica Thorne
Sources: Antipsychotic drug exhibits cancer-fighting properties: www.cancer.gov/newscenter/cancerresearchnews/2013/AntipsychoticDrugCancerFightingProperties; Gutierrez A, Pan L, Groen RWJ et al. Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J. Clin. Invest. 124(2), 644–655 (2014).
Researchers at National Tsing Hua University (Hsinchu, Taiwan) have reported that gold nanorods can mediate photodynamic destruction of tumors upon near-infrared light irradiation.
Currently, photodynamic therapy is limited due to the inability of light to penetrate deep tissue, which is essential to activate the photosensitizer that then kills cancer cells. However, according to the report, gold nanorods alone “can sensitize formation of singlet oxygen and exert dramatic photodynamic therapy effects on complete destruction of tumors in mice under very low LED/laser doses.”
The team, led by Kuo Chu Hwang, confirmed its findings in B16F0 melanoma tumors in mice. The gold nanorods were able to destruct tumors without the addition of organic photosensitizers. The ability of these gold nanorods to kill cancer cells was compared with doxorubicin, an anticancer drug currently used in the clinic, and were demonstrated to be more effective. Furthermore, the study demonstrated that the gold nanorods emit single photon-induced fluorescence, which allows in vivo visualization of localization and distribution.
– Written by Jessica Thorne
Source: Vankayala R, Huang YK, Kalluru P, Chiang CS, Hwang KC. First demonstration of gold nanorods-mediated photodynamic therapeutic destruction of tumors via near infra-red light activation. Small doi:10.1002/smll.201302719 (2014) (Epub ahead of print).