Synergistically Anti-Multiple Myeloma Effects: Flavonoid, Non-Flavonoid Polyphenols, and Bortezomib

Abstract

Multiple myeloma (MM) is a clonal plasma cell tumor originating from a post-mitotic lymphoid B-cell lineage. Bortezomib(BTZ), a first-generation protease inhibitor, has increased overall survival, progression-free survival, and remission rates in patients with MM since its clinical approval in 2003. However, the use of BTZ is challenged by the malignant features of MM and drug resistance. Polyphenols, classified into flavonoid and non-flavonoid polyphenols, have potential health-promoting activities, including anti-cancer. Previous preclinical studies have demonstrated the anti-MM potential of some dietary polyphenols. Therefore, these dietary polyphenols have the potential to be alternative therapies in anti-MM treatment regimens. This systematic review examines the synergistic effects of flavonoids and non-flavonoid polyphenols on the anti-MM impacts of BTZ. Preclinical studies on flavonoids and non-flavonoid polyphenols-BTZ synergism in MM were collected from PubMed, Web of Science, and Embase published between 2008 and 2020. 19 valid preclinical studies (Published from 2008 to 2020) were included in this systematic review. These studies demonstrated that eight flavonoids (icariin, icariside II, (-)-epigallocatechin-3-gallate, scutellarein, wogonin, morin, formononetin, daidzin), one plant extract rich in flavonoids (Punica granatum juice) and four non-flavonoid polyphenols (silibinin, resveratrol, curcumin, caffeic acid) synergistically enhanced the anti-MM effect of BTZ. These synergistic effects are mediated through the regulation of cellular signaling pathways associated with proliferation, apoptosis, and drug resistance. Given the above, flavonoids and non-flavonoid polyphenols can benefit MM patients by overcoming the challenges faced in BTZ treatment. Despite the positive nature of this preclinical evidence, some additional investigations are still needed before proceeding with clinical studies. For this purpose, we conclude by providing some suggestions for future research directions.

Metformin and chidamide synergistically suppress multiple myeloma progression and enhance lenalidomide/bortezomib sensitivity

“…However, drug efficacy is challenged by acquired drug resistance in MM. 29,39 Treatment with metformin or chidamide has been reported to sensitize MM cells to bortezomib or lenalidomide. 17,30,40 Induction of cell cycle arrest and programmed cell death such as apoptosis and autophagy is a promising strategy for anticancer treatment.…”

“…A combination of an immunomodulatory drug such as lenalidomide and proteasome inhibitor such as bortezomib is usually recommended for MM patients. However, drug efficacy is challenged by acquired drug resistance in MM 29,39 . Treatment with metformin or chidamide has been reported to sensitize MM cells to bortezomib or lenalidomide 17,30,40 .…”

Wogonin, as a potent anticancer compound: From chemistry to cellular interactions

“…There is evidence that the compound in combination with a first-generation protease inhibitor, Bortezomib (BTZ), in a clonal plasma cell tumor, multiple myeloma (MM) regulated by signaling cascades linked with tumor growth, medication resistance, and apoptosis. 60 Furthermore, it was investigated that wogonin potentiates TRAIL-induced growth inhibition and tumor cell death in A549 cancerous cells, as shown by the TUNEL assay. 61 In addition, it was also demonstrated that wogonin therapy reinstates the TRAIL-mediated apoptosis in the presence of ROS by upregulating p53 and PUMA in TRAIL-resistant cancer cells.…”

Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives

“…Treatment with bortezomib enhances the bone marrow microenvironment by stimulating the development of osteoblasts and decreasing the activity of osteoclasts that depend on the receptor activator of NF-κB (RANKL). This effect is achieved through the activation of NF-κB, p38, and AP-1 pathways, and is influenced by the dosage of bortezomib [ 100 ]. The Phase I clinical trial study (NCT00858234) revealed that the most predominant adverse events were thrombocytopenia, leukopenia, neutropenia, diarrhea, nausea, decreased appetite, and vomiting [ 101 ].…”