Dual Inhibition of Ornithine Decarboxylase and A1 Adenosine Receptor Efficiently Suppresses Breast Tumor Cells

Abstract

Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.

Cancer‐related somatic mutations alter adenosine A 1 receptor pharmacology—A focus on mutations in the loops and C‐terminus

“…55 Moreover, preclinical observations showed that hA 1 AR blockade by DPCPX inhibits cancer cell proliferation and promotes cell apoptosis. 15,56,57 Mutant receptors with altered receptorligand interaction, for example N148S EL2 , V152L EL2 , and M177V 5.35 in this study, may thus result in mis-dosing while using these small molecules as therapeutic approaches. Studies on GPCR heteromers provided evidence for the presence of hA 1 AR.…”

A Combination of Cytokine-Induced Killer Cells With PD-1 Blockade and ALK Inhibitor Showed Substantial Intrinsic Variability Across Non-Small Cell Lung Cancer Cell Lines

“…The combined use of therapeutic agents within combination therapy has proven to be advantageous (over monotherapy) in several ways, such as enhanced efficacy, reduced side effects, and minimal drug resistance. Of clinical importance, several cancers have been reported to optimize this therapeutic approach, such as renal cell carcinoma, melanoma, Hodgkin’s lymphoma, and breast cancer to name a few ( 31 – 34 ). In particular, non-small cell lung cancer (NSCLC) is one of the prominent cancers where a number of studies documenting the clinical outcomes of mono and/or combination therapies have been reported ( ).…”

DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment

“…Earlier studies in genetic mouse models of KRAS mutant pancreatic cancer showed the potential of using DFMO as a chemoprevention agent [20]. Additionally, DFMO has shown preclinical success in various cancer models [16,17,[23][24][25][26]. Most notably, DFMO has been successfully used in multiple clinical trials to treat neuroblastoma [16,17,27].…”