Prospective pilot trial with combination of propranolol with chemotherapy in patients with epithelial ovarian cancer and evaluation on circulating immune cell gene expression

Ramondetta, Lois M.; Hu, Wei; Thaker, Premal H.; Urbauer, Diana L.; Chisholm, Gary B.; Westin, Shannon N.; Sun, Yunjie; Ramírez, Pedro T.; Fleming, Nicole D.; Sahai, Sunil K.; Nick, Alpa M.; Arevalo, Jesusa M.G.; Dizon, Thomas; Coleman, Robert L.; Cole, Steve W.; Sood, Anil K.

doi:10.1016/j.ygyno.2019.07.004

Cited by 34 publications

(35 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Authors have extensively detailed and elucidated mechanisms contributing to β adrenergic receptor modulated signaling, dynamics, and regulation [11-16, 47, 154], pharmacological modulation of which may powerfully modify tumor cell proliferation, motility, immunogenicity, elaboration of protein mediators promoting angiogenesis, and invasive and metastatic potential [124,154]. Studies have alternately demonstrated amplification or attenuation of cellular proliferation of gliomas [6,39,40] and extra-neuraxial carcinomas in response to pharmacological enhancement of β adrenergic receptor modulated signaling [8,45,46,49,51,52,54,57,63,152]. The character of βagonist utilized, tumor model and preparation type, receptor regulation dynamics, and differential distal signal transduction mechanisms may explain inter-experimental differences.…”

Section: Discussionmentioning

confidence: 99%

“…Succinctly, blunting of tumor cell proliferation in vitro by β adrenergic agonists results from desensitization and by β adrenergic antagonists results directly from receptor antagonism [62]. Studies have alternately demonstrated improved [63] or reduced [64] survival in patients harboring ovarian carcinoma receiving pharmacological antagonists of β adrenergic receptors. The bitopic agonist and GPR55 antagonist ( , ' )-4′-methoxy-1-naphthylfenoterol, which may be designated as ( , ' )-MNF, significantly reduces mitogenic potential in melanoma by modulating cyclic AMP protein kinase A-dependent pathways [65].…”

Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

See 1 more Smart Citation

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

View full text Add to dashboard Cite

Neoplastically transformed astrocytes express functionally active cell surface β adrenergic receptors (βARs). Treatment of glioma models in vitro and in vivo with β adrenergic agonists variably amplifies or attenuates cellular proliferation. In the majority of in vivo models, β adrenergic agonists generally reduce cellular proliferation. However, treatment with β adrenergic agonists consistently reduces tumor cell invasive potential, angiogenesis, and metastasis. β adrenergic agonists induced decreases of invasive potential are chiefly mediated through reductions in the expression of matrix metalloproteinases types 2 and 9. Treatment with β adrenergic agonists also clearly reduce tumoral neoangiogenesis, which may represent a putatively useful mechanism to adjuvantly amplify the effects of bevacizumab. Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor receptor. We may accordingly designate βagonists to represent an enhancer of bevacizumab. The antiangiogenic effects of β adrenergic agonists may thus effectively render an otherwise borderline effective therapy to generate significant enhancement in clinical outcomes. β adrenergic agonists upregulate expression of the major histocompatibility class II DR alpha gene, effectively potentiating the immunogenicity of tumor cells to tumor surveillance mechanisms. Authors have also demonstrated crossmodal modulation of signaling events downstream from the β adrenergic cell surface receptor and microtubular polymerization and depolymerization. Complex effects and desensitization mechanisms of the β adrenergic signaling may putatively represent promising therapeutic targets. Constant stimulation of the β adrenergic receptor induces its phosphorylation by β adrenergic receptor kinase (βARK), rendering it a suitable substrate for alternate binding by β arrestins 1 or 2. The binding of a β arrestin to βARK phosphorylated βAR promotes receptor mediated internalization and downregulation of cell surface receptor and contemporaneously generates a cell surface scaffold at the βAR. The scaffold mediated activation of extracellular regulated kinase 1/2, compared with protein kinase A mediated activation, preferentially favors cytosolic retention of ERK1/2 and blunting of nuclear translocation and ensuant pro-transcriptional activity. Thus, βAR desensitization and consequent scaffold assembly effectively retains the cytosolic homeostatic functions of ERK1/2 while inhibiting its pro-proliferative effects. We suggest these mechanisms specifically will prove quite promising in developing primary and adjuvant therapies mitigating glioma growth, angiogenesis, invasive potential, and angiogenesis. We suggest generating compounds and targeted mutations of the β adrenergic receptor favoring β arrestin binding and scaffold facilitated activation of ERK1/2 may hold potential promise and therapeutic benefit in adjuvantly treating most or all cancers. We hope our discussion will generate fruitful research endeavors seeking to exploit these mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Modulation Of Cellular Proliferation By β Adrenergic Signalingmentioning

confidence: 99%

RETRACTED ARTICLE: β adrenergic receptor modulated signaling in glioma models: promoting β adrenergic receptor-β arrestin scaffold-mediated activation of extracellular-regulated kinase 1/2 may prove to be a panacea in the treatment of intracranial and spinal malignancy and extra-neuraxial carcinoma

Ghali

2020

Mol Biol Rep

View full text Add to dashboard Cite

show abstract

“…Altered psychological states, such as chronic stress or depression, affect the quality of life of EOC patients and can also promote tumor progression and influence treatment outcomes [3][4][5][6][7][8][9]. Notably, a significant number of EOC patients lack social support, are clinically depressed, or exhibit anxiety disorders [4,10,11].…”

Section: Introductionmentioning

confidence: 99%

Norepinephrine-Induced DNA Damage in Ovarian Cancer Cells

Lamboy-Caraballo

Ortiz-Sanchéz²,

Acevedo‐Santiago

et al. 2020

IJMS

View full text Add to dashboard Cite

Multiple studies have shown that psychological distress in epithelial ovarian cancer (EOC) patients is associated with worse quality of life and poor treatment adherence. This may influence chemotherapy response and prognosis. Moreover, although stress hormones can reduce cisplatin efficacy in EOC treatment, their effect on the integrity of DNA remains poorly understood. In this study, we investigated whether norepinephrine and epinephrine can induce DNA damage and modulate cisplatin-induced DNA damage in three EOC cell lines. Our data show that norepinephrine and epinephrine exposure led to increased nuclear γ-H2AX foci formation in EOC cells, a marker of double-strand DNA breaks. We further characterized norepinephrine-induced DNA damage by subjecting EOC cells to alkaline and neutral comet assays. Norepinephrine exposure caused DNA double-strand breaks, but not single-strand breaks. Interestingly, pre-treatment with propranolol abrogated norepinephrine-induced DNA damage indicating that its effects may be mediated by β-adrenergic receptors. Lastly, we determined the effects of norepinephrine on cisplatin-induced DNA damage. Our data suggest that norepinephrine reduced cisplatin-induced DNA damage in EOC cells and that this effect may be mediated independently of β-adrenergic receptors. Taken together, these results suggest that stress hormones can affect DNA integrity and modulate cisplatin resistance in EOC cells.

show abstract

“…Epithelial ovarian cancer (EOC) is the primary cause of unique cancer-related death in women. Patients with early stage, local tumours can be successfully treated with surgery combined with adjuvant therapy [1]. However, most ovarian cancer patients are diagnosed at an advanced stage with distant metastases that cannot be removed; the effects of these treatments are frequently temporary [2], and 80% of patients with late stage disease experience recurrence and advance to the fatal phase as a results of insensitivity to chemotherapy, distant metastasis and poor prognosis [3].…”

Section: Introductionmentioning

confidence: 99%

T-cadherin in epithelial ovarian cancer: relationship with cancer progression and drug resistanceT-cadherin in epithelial ovarian cancer: relationship with cancer progression and drug resistance

Guan

Lin

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: T-cadherin plays a crucial role in maintaining normal tissue structure by regulating specific cell adhesion, cellular recognition and signal transduction. The purpose of this study was to evaluate whether T-cadherin influences epithelial ovarian cancer (EOC) progression, differentiation and drug resistance and its possible mechanisms.Methods: Epithelial ovarian carcinoma (EOC, n=63) and relevant contralateral normal ovarian (CNO, n=41) fresh tissues were collected from epithelial ovarian carcinoma patients, and benign ovarian tumour fresh tissues were collected from 55 patients with benign ovarian tumours. The human epithelial ovarian carcinoma cell line A2780 was cultured. T-cadherin expression was assessed by real-time RT-PCR and Western blotting, and the expression of matrix metalloproteinase-2 (MMP-2) was detected by Western blotting. pcDNA‑T‑cad plasmid technology was used to upregulate T-cadherin expression. In addition, A2780 cell migration and invasion ability, viability, colony formation, proliferation, apoptosis and sensitivity to paclitaxel were measured.Results: T‑cadherin mRNA and protein expression in EOC tissues from EOC patients was significantly downregulated, and there was no significant difference between the matched contralateral normal ovarian fresh tissue from the same patient and the benign ovarian tumour tissues from other patients. The migration and invasion abilities, viability, colony formation, and proliferation were attenuated by restoration of T‑cadherin expression in A2780 cells via pcDNA‑T‑cad transfection; apoptosis, MMP-2 expression and sensitivity to Taxol were also enhanced by restored T‑cadherin expression. The T‑cadherin expression level was well correlated with the clinical characteristics and symptoms of EOC patients, including tumour stage, histology, lymph node metastasis, tumour size, distant metastasis and cisplatin resistance.Conclusions: T‑cadherin participates in the processes of epithelial ovarian carcinoma cell migration, invasion, proliferation, apoptosis and sensitivity to paclitaxel and can regulate the expression of MMP-2. Downregulation of T‑cadherin expression may contribute to epithelial ovarian cancer progression, differentiation and drug resistance.

show abstract

Prospective pilot trial with combination of propranolol with chemotherapy in patients with epithelial ovarian cancer and evaluation on circulating immune cell gene expression

Cited by 34 publications

References 38 publications

Norepinephrine-Induced DNA Damage in Ovarian Cancer Cells

T-cadherin in epithelial ovarian cancer: relationship with cancer progression and drug resistanceT-cadherin in epithelial ovarian cancer: relationship with cancer progression and drug resistance

Contact Info

Product

Resources

About