Abstract
Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility.
Highlights
These findings firstly propose chlorogenic acid (CGA) as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 mitogen-activated protein kinase (MAPK) pathway as relevantly involved in CGA-mediated
In accordance with our previous findings [23], Figure 1A shows a different responsiveness to CGA between U2OS and MG-63, the latter recognized as the least sensitive model
Among the pharmacological approaches conceived to overcome both Doxo resistance and toxicity, combination therapy surely represents the most-used regimen for treating cancer patients in an advanced state
Summary
While it is undeniable that more innovative and accurate pharmacological approaches are constantly tested in preclinical cancer models, even exhibiting promising results, chemotherapy still represents the only partially effective treatment for certain tumor types, as well as tumor stages, in clinical practice [1].Even though this class of medications displays a high response rate in first-line regime, prolonged administration is often associated with resistance and side-effect occurrence [2,3].Such outcomes are especially prominent when anthracyclines are chronically employed in managing high-grade and metastatic malignancies [4].As the most extensively used anthracyclines, doxorubicin (Doxo) is currently approved to treat several neoplastic disorders including breast and gynecologic tumors, lymphoma, and lung cancer [5]. While it is undeniable that more innovative and accurate pharmacological approaches are constantly tested in preclinical cancer models, even exhibiting promising results, chemotherapy still represents the only partially effective treatment for certain tumor types, as well as tumor stages, in clinical practice [1]. Even though this class of medications displays a high response rate in first-line regime, prolonged administration is often associated with resistance and side-effect occurrence [2,3]. Disrupting both DNA synthesis and replication, Doxo induces cancer cell death in multiple ways, which mainly affect topoisomerase II poisoning and DNA base pair intercalation [7]
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