Interaction of Adenosine, Modified Using Carborane Clusters, with Ovarian Cancer Cells: A New Anticancer Approach against Chemoresistance

Abstract

Platinum compounds remain the first-line drugs for the treatment of most lethal gynecological malignancies and ovarian cancers. Acquired platinum resistance remains a major challenge in gynecological oncology. Considering the unique physicochemical properties of the metallacarboranes modifier and the significant role of nucleoside derivatives as anticancer antimetabolites, we designed and synthesized a set of adenosine conjugates with metallacarboranes containing iron, cobalt, or chromium as semi-abiotic compounds that influence the cisplatin sensitivity of ovarian cancer cells. Adherent cultures of ovarian carcinoma cell lines and multicellular spheroids, ranging from sensitive to highly resistant including experimental cell lines “not responding” to platinum drugs were used. Iron-containing metallacarborane conjugates showed the best anticancer activity, especially against resistant cells. Compound modified at the C2′ nucleoside position showed the best activity in resistant cancer cells and highly resistant cancer spheroids exposed to cisplatin, increasing cell cycle arrest, apoptosis or necrosis, and reactive oxygen species production. Moreover, it showed high cellular accumulation and did not induce cross-resistance to cisplatin, carboplatin, doxorubicin, paclitaxel, or gemcitabine in long-term cultures. The reference nido-carborane derivative (no metal ions) and unmodified nucleosides were not as effective. These findings indicate that metallacarborane modification of adenosine may sensitize ovarian cancer cells to cisplatin in combination treatment.

Recent Development of Radiofluorination of Boron Agents for Boron Neutron Capture Therapy of Tumor: Creation of 18F-Labeled C-F and B-F Linkages

“…Of the boron-containing agents reported so far, boronophenylalanine (BPA) and borocaptate sodium (BSH) are the two most commonly used boron agents for clinical treatment ( Figure 1 ). In addition, various boron agents have been developed in the past decades, including peptides [ 27 , 28 ], antibody-based delivery systems [ 29 , 30 ], boron compound conjugates [ 31 , 32 ], boron-containing nanoparticles [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], boric acid [ 41 , 42 , 43 ], and decahydrodecaborate (GB-10) [ 44 , 45 ].…”

Physico‐chemical Properties and Anticancer Activity of Carborane‐BODIPY Conjugates: A Review

“…However, the therapeutic dose of at least 20μg 10 B/g tumor is required for effective BNCT treatment. Although BNCT have been primarily used for the treatment of fatal malignant brain cancers such as glioblastoma multiforme, [25] it is now being applied to the treatment of highly grade other types of cancers such as melanoma, [26] ovarian cancer, [27] head and neck cancer [28] . There are a number of reviews available on the synthesis of carborane derivatives as boron delivery platforms and their various medicinal applications [24,29,30] …”

A3 Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity

“…In this regard, the mechanisms that influence the cancer cells' proliferation or death could also be due to the modulation of Ado levels, which can be modified by affecting the pathways of Ado generation, degradation, and elimination [11,12]. Furthermore, A 3 AR ligands conjugated with metallacarborans, containing iron and cobalt, protect cells from cross-resistance showed by anticancer drugs such as cisplatin, carboplatin, and doxorubicin [13,14].…”

“…Anal (C 32 H 29 N 5 O 4 ) C, H, N. 3.1.8. Synthesis of 2,6-Dichloro-2 ,3 ,5 -tri-O-acetyl-(β-D-ribofuranosyl)purine(14)…”