Multiple Myeloma Inhibitory Activity of Plant Natural Products

Jöhrer, Karin; Ҫiҫek, Serhat Sezai

doi:10.3390/cancers13112678

Cited by 16 publications

(10 citation statements)

References 220 publications

(281 reference statements)

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“…Overall, our data demonstrate that RHM has powerful anti-MM activity by targeting LIG3-driven DNA repair and confirm that MM cells are Alt-NHEJ-MYC-addicted. Even if a variety of natural compounds have shown antitumor activity in preclinical models of MM [ 78 , 79 ], in this study, we provide the first evidence of anti-MM activity induced by RHM, selected after an unbiased multistep screen path, and functionally validated.…”

Section: Discussionmentioning

confidence: 99%

Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin

et al. 2022

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Background DNA ligases are crucial for DNA repair and cell replication since they catalyze the final steps in which DNA breaks are joined. DNA Ligase III (LIG3) exerts a pivotal role in Alternative-Non-Homologous End Joining Repair (Alt-NHEJ), an error-prone DNA repair pathway often up-regulated in genomically unstable cancer, such as Multiple Myeloma (MM). Based on the three-dimensional (3D) LIG3 structure, we performed a computational screening to identify LIG3-targeting natural compounds as potential candidates to counteract Alt-NHEJ activity in MM. Methods Virtual screening was conducted by interrogating the Phenol Explorer database. Validation of binding to LIG3 recombinant protein was performed by Saturation Transfer Difference (STD)—nuclear magnetic resonance (NMR) experiments. Cell viability was analyzed by Cell Titer-Glo assay; apoptosis was evaluated by flow cytometric analysis following Annexin V-7AAD staining. Alt-NHEJ repair modulation was evaluated using plasmid re-joining assay and Cytoscan HD. DNA Damage Response protein levels were analyzed by Western blot of whole and fractionated protein extracts and immunofluorescence analysis. The mitochondrial DNA (mtDNA) copy number was determined by qPCR. In vivo activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells. Results Here, we provide evidence that a natural flavonoid Rhamnetin (RHM), selected by a computational approach, counteracts LIG3 activity and killed Alt-NHEJ-dependent MM cells. Indeed, Nuclear Magnetic Resonance (NMR) showed binding of RHM to LIG3 protein and functional experiments revealed that RHM interferes with LIG3-driven nuclear and mitochondrial DNA repair, leading to significant anti-MM activity in vitro and in vivo. Conclusion Taken together, our findings provide proof of concept that RHM targets LIG3 addiction in MM and may represent therefore a novel promising anti-tumor natural agent to be investigated in an early clinical setting.

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Section: Discussionmentioning

confidence: 99%

Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin

et al. 2022

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“…These polyphenolic compounds also have the potential to reduce BTZ resistance. Given the low toxicity of natural polyphenolic compounds, their synergistic combination with BTZ may offer MM patients extra therapeutic options [ 19 , 20 ].…”

Section: Exploration Of Synergistic Drug Combinations In MM Therapymentioning

confidence: 99%

“…In addition, the cancer prevention and treatment potential of some non-flavonoid polyphenols are equally noteworthy [ 17 , 18 ]. Jöhrer and Pojero reviewed the tumor activity inhibition and targeting cancer effects of some natural compounds (including polyphenols) in MM in preclinical trials, respectively [ 19 , 20 ]. As mentioned earlier, the main challenge MM drug interventions face is drug resistance.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…In recent years, a considerable body of scientific evidence has underlined the promising potential of bioactive ingredients derived from TCMMs for treatment of MM. To the best of our knowledge, there is no systematic summary of the anti-MM effects and clinical applications of these commonly utilized bioactive components extracted from TCMMs that are different from the natural products reviewed by Jöhrer et al (Jöhrer and Ҫiҫek, 2021). The objective of this review was to systematically summarize the available evidence of the anti-MM effects of the bioactive components isolated from TCMMs and to identify future research priorities for the development of novel agents for MM.…”

Section: Introductionmentioning

confidence: 99%

Active Components of Traditional Chinese Medicinal Material for Multiple Myeloma: Current Evidence and Future Directions

Cheng

et al. 2022

Front. Pharmacol.

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Multiple myeloma (MM) is a hematological malignancy characterized by clonal expansion of plasma cells in bone marrow, leading to the overproduction of monoclonal immunoglobulins. The clinical manifestations resulting from monoclonal proteins and malignant cells include signs of end-organ damage, such as hypercalcemia, renal failure, anemia, and bone lesions. Despite improvement in the survival of MM patients with use of myeloma-targeted and immunomodulatory therapies, MM remains an incurable disease. Moreover, patients with relapsed or refractory MM show poor survival outcomes. In recent years, there has been a growing interest in the use of traditional Chinese medicinal materials (TCMMs) for management of a wide spectrum of diseases. The bioactive ingredients derived from TCMMs hold great potential for the development of anticancer drugs. Here we summarize the evidence of the pharmacological effects of the active components in TCMMs on MM, including curcumin, resveratrol, baicalein, berberine, bufalin, cinobufagin, gambogic acid, ginsenoside, icariin, daidzin, formononetin, polysaccharides extracts from Hedyotis difus, and scutellarein. Available evidence indicates that the anti-MM effects of these bioactive ingredients are mediated via regulation of proliferation, apoptosis, autophagy, cell cycle, osteogenic differentiation, and drug resistance. In the future, the underlying mechanisms of the anti-MM effects of these components should be further investigated. Large-scale and well-designed clinical trials are also required to validate the efficacy of these bioactive constituents for MM.

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Multiple Myeloma Inhibitory Activity of Plant Natural Products

Cited by 16 publications

References 220 publications

Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin

Exploiting DNA Ligase III addiction of multiple myeloma by flavonoid Rhamnetin

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

Active Components of Traditional Chinese Medicinal Material for Multiple Myeloma: Current Evidence and Future Directions

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