Promoter polymorphisms in the β-2 adrenergic receptor are associated with drug-induced gene expression changes and response in acute lymphoblastic leukemia

We investigated whether genetic polymorphisms in the promoter region of the proapoptotic β-2 adrenergic receptor gene (ADRB2) influence treatment-induced changes in ADRB2 expression in leukemia cells and response to chemotherapy. The ADRB2 promoter region was genotyped in germline DNA from 369 children with acute lymphoblastic leukemia (ALL). For 95 of the patients, sufficient RNA was available before and after in vivo treatment to assess treatment-induced gene expression changes in ALL cells. After treatment, the median ADRB2 mRNA expression was ninefold lower in leukemia cells of patients who ultimately relapsed as compared with patients who remained in continuous complete remission (CCR). Polymorphisms in the ADRB2 promoter were significantly linked to methotrexate (MTX)-induced upregulation in ADRB2 gene expression in ALL cells. Moreover, the ADRB2 promoter haplotype was significantly related to early treatment response in 245 children with ALL who received uniform treatment. We conclude that germline polymorphisms in ADRB2 are linked to the antileukemic effects of ALL chemotherapy.     

Dental abnormalities after chemotherapy in long-term survivors of childhood acute lymphoblastic leukemia 7–40 years after diagnosis

Purpose

Factors associated with the long-term dental effects after chemotherapy for childhood malignancies have not been well described. The primary aims of this study were as follows: (1) to assess whether age at diagnosis and treatment-related factors are associated with dental defects in survivors of childhood acute lymphoblastic leukemia (ALL) and (2) to assess the survivors’ annual expenses for dental treatment compared to reference data.

Methods

This cross-sectional study enrolled 111 Norwegian survivors of ALL diagnosed before the age of 16. All of the subjects completed a questionnaire and underwent medical and oral examinations. Dental defects were registered according to the individual defect index, with 0 = no defects and 140 = anodontia, and the caries experience was registered according to the decayed-missing-filled teeth index (DMFT). Age-matched reference data were drawn from a national general population survey (n = 555).

Results

The mean age at examination was 29.1 years (SD 7.2), and mean follow-up period was 22.9 years (SD 7.3). In a regression model, diagnoses occurring at ≤5 years of age (B = ?9.6, p < 0.001) and a cumulative dose of anthracyclines >120 mg/m² (B = 11.5, p < 0.001) were strongly associated with more severe dental defects. Survivors treated after the age of 5 had experienced more caries than those treated at a younger age [DMFT 9.6 (SD 6.1) vs. 6.0 (SD 4.6), respectively; p = 0.001]. High annual expenses for dental treatment were reported by a larger percentage of the reference population compared to the survivor group (18 vs. 9 %, respectively; p = 0.02).

Conclusions

The age at diagnosis and the dose of anthracyclines appear to be strongly associated with the severity of dental defects, although few survivors reported high annual expenses for dental treatment. The increased risk of dental defects during adulthood should be communicated to ALL survivors.

     

Chemokine-dependent B cell–T cell interactions in chronic lymphocytic leukemia and multiple myeloma – targets for therapeutic intervention?

Introduction: Chemokines and their receptors play essential roles in the development, maintenance and proper functioning of the immune system. B cell–T cell interactions are modulated by chemokines. In B cell malignancies, these interactions may have tumor-promoting consequences.

Areas covered: This review summarizes physiological B cell–T cell interactions and discusses their pathological role in the onset and progression of B cell malignancies with a special focus on chronic lymphocytic leukemia and multiple myeloma. Experimental data on chemokine-guided B cell-T cell actions in B cell malignancies from murine models as well as in vitro data are summarized and their potential as future therapeutic targets is critically discussed.

Expert opinion: Direct or indirect targeting of chemokine receptors involved in localization and T-cell-dependent activation of B lymphocytes can provide strong synergisms with conventional or immunomodulatory therapies by disrupting the microenvironmental conditions necessary for survival and proliferation of malignant B lymphocytes. However, further knowledge of these interactions between B and T cells is needed.     

Transient, 5-HT2B receptor–mediated facilitation in neuropathic pain: Up-regulation of PKCγ and engagement of the NMDA receptor in dorsal horn neurons

Spinal nociception can be facilitated by 5-HT2 receptors in neuropathic pain. We investigated the involvement of glutamate receptors in dorsal neuron hyperexcitation that is promoted by 5-HT2B receptor (5-HT2BR) after spinal nerve ligation (SNL) in the rat. Augmentation of C-fiber–evoked potentials by spinal superfusion with 5-HT2BR agonist BW 723C86 in nerve-ligated rats was impeded by co-administration of NMDA receptor (NMDAR) antagonist D-AP5, but not by mGluR1/5 antagonist AIDA or mGluR2/3 antagonist LY 341495. Evoked potentials were increased by cis-ACPD in nerve-injured rats, irrespective of simultaneous 5-HT2BR blockade by SB204741. In uninjured rats, NMDAR agonist cis-ACPD enhanced evoked potentials in the presence of BW 723C86 but not if administered alone or during exposure to protein kinase C γ (PKCγ) inhibitor peptide. Triple immunofluorescence labelings revealed co-localization of NMDAR and 5-HT2BR in PKCγ-expressing perikarya in lamina II neurons. As a result of SNL, PKCγ was transiently and bilaterally up-regulated in synaptic fraction from dorsal horn homogenates, peaking at day 2 and returning to basal levels by day 9. Chronic blockade of 5-HT2BR with selective antagonist SB 204741 after SNL bilaterally decreased the following: (i) PKCγ up-regulation in synaptic fraction, (ii) phosphorylation of NMDAR subunit NR1 (serine 889) in synaptic fraction, and (iii) co-localization of both PKCγ and phosphorylated NR1 with postsynaptic marker PSD-95. Chronic delivery of SB 204741 bilaterally attenuated thermal and mechanical allodynia occurring after SNL, particularly at day 2 post injury. These findings suggest that transient activation of the PKCγ/NMDAR pathway is critically involved in 5-HT2BR-mediated facilitation in the SNL model of neuropathic pain.     

The inhibition of PI3K and NFκB promoted curcumin-induced cell cycle arrest at G2/M via altering polyamine metabolism in Bcl-2 overexpressing MCF-7 breast cancer cells

Bcl-2 protein has been contributed with number of genes which are involved in oncogenesis. Among the many targets of Bcl-2, NFκB have potential role in induction of cell cycle arrest. Curcumin has potential therapeutic effects against breast cancer through multiple signaling pathways. In this study, we investigated the role of curcumin in induction of cell cycle arrest via regulating of NFκB and polyamine biosynthesis in wt and Bcl-2+ MCF-7 cells. To examine the effect of curcumin on cell cycle regulatory proteins, PI3K/Akt, NFκB pathways and polyamine catabolism, we performed immunoblotting assay. In addition, cell cycle analysis was performed by flow cytometry. The results indicated that curcumin induced cell cycle arrest at G2/M phase by downregulation of cyclin B1 and Cdc2 and inhibited colony formation in MCF-7 wt cells. However, Bcl-2 overexpression prevented the inhibition of cell cycle associated proteins after curcumin treatment. The combination of LY294002, PI3K inhibitor, and curcumin induced cell cycle arrest by decreasing CDK4, CDK2 and cyclin E2 in Bcl-2+ MCF-7 cells. Moreover, LY294002 further inhibited the phosphorylation of Akt in Bcl-2+ MCF-7 cells. Curcumin could suppress the nuclear transport of NFκB through decreasing the interaction of P-IκB-NFκB. The combination of wedelolactone, NFκB inhibitor, and curcumin acted different on SSAT expression in wt MCF-7 and Bcl-2+ MCF-7 cells. NFκB inhibition increased the SSAT after curcumin treatment in Bcl-2 overexpressed MCF-7 cells. Inhibition of NFκB activity as well as suppression of ROS generation with NAC resulted in the partial relief of cells from G2/M checkpoint after curcumin treatment in wt MCF-7 cells. In conclusion, the potential role of curcumin in induction of cell cycle arrest is related with NFκB-regulated polyamine biosynthesis.