Abstract
Multiple myeloma (MM) is one of the most widespread hematological cancers. It is characterized by a clonal proliferation of malignant plasma cells in the bone marrow and by the overproduction of monoclonal proteins. In recent years, the survival rate of patients with multiple myeloma has increased significantly due to the use of transplanted stem cells and of the new therapeutic agents that have significantly increased the survival rate, but it still cannot be completely cured and therefore the development of new therapeutic products is needed. Moreover, many patients have various side effects and face the development of drug resistance to current therapies. The purpose of this review is to highlight the bioactive active compounds (flavonoids) and herbal extracts which target dysregulated signaling pathway in MM, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their healing potential targeting multiple myeloma. Mechanistically, they demonstrated the ability to promote cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration/tumor progression, inhibition of angiogenesis in the tumor vascular network. Current research provides valuable new information about the ability of flavonoids to enhance the apoptotic effects of antineoplastic drugs, thus providing viable therapeutic options based on combining conventional and non-conventional therapies in MM therapeutic protocols.
Highlights
Multiple myeloma (MM) is one of the most widespread hematological cancers
Activated signal transducer activation and transcriptional activator 3 (STAT3) induced transcription of target genes leads to increased survival, proliferation and drug resistance of MM cells: Src homology containing protein 1 (SHP-1), suppressor of cytokine signaling 1 (SOCS1), estrogen receptor (ER), Janus Associated kinase (JAK), phosphatase of regenerating liver 3 (PRL3), and peroxisome proliferator activated receptors (PPAR) [83]
They represent a large group of water-soluble antioxidant compounds, which frequently occur in plants as glycosides and consist of two aromatic rings linked by a carbon bond and form a heterocyclic ring [96]
Summary
MTOR, JAK/STAT3, NF-κB) are involved in MM, as well as extracellular mediators (TNFα, IL8, TGFβ1, (IL6, FGF-2, PDGF, IGF, VEGF) [60]. Bcl-2 family proteins (Bax, Bad, and Bcl-2) are the major regulators of apoptotic processes and play a key role in mitochondrial-mediated apoptosis [62,63]. Activation of Bcl-2 pathways may regulate mitochondrial-mediated apoptosis. Phosphorylated Akt binds to PI3K-activated products, and inhibit the pro-apoptotic factors of caspase-3, -9, and Bad [71]. Activated STAT3 induced transcription of target genes leads to increased survival, proliferation and drug resistance of MM cells: Src homology containing protein 1 (SHP-1), suppressor of cytokine signaling 1 (SOCS1), estrogen receptor (ER), Janus Associated kinase (JAK), phosphatase of regenerating liver 3 (PRL3), and peroxisome proliferator activated receptors (PPAR) [83]. Mitogen-activated protein kinase (MAPK) is a cell survival regulator, and Jun Nterminal kinase (JNK) signaling is a component of this pathway. The best strategy for the treatment of MM is a single agent or combination of molecules targeting several dysregulated signaling pathways
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