Basic Research

The inhibitory effect and molecular mechanism of 6-gingerol on human multiple myeloma cells

  • Chunfang KONG ,
  • Anna LI ,
  • Bo KE ,
  • Weirong DING ,
  • Tingting LIU ,
  • Huan FU ,
  • Tingting ZHANG ,
  • Chenghao JIN ,
  • Mei. WU
Expand
  • *.Department of Hematology,Jiangxi Provincial People′s Hospital,the First Affiliated Hospital of Nanchang Medical College,Nanchang 330006,Jiangxi,China
    *.Jiangxi Province Key Laboratory of Hematologic Diseases,Nanchang 330006,Jiangxi,China

Received date: 2024-08-01

  Online published: 2024-12-16

Abstract

Objective To investigate the inhibitory effect and elucidate the molecular mechanism of 6?gingerol on human multiple myeloma cells. Methods The human multiple myeloma cell lines RPMI 8226 and ARH77 were cultured in vitro, followed by treatment with varying concentrations (50, 100, 200, 300, 400 μmol/L) of 6?gingerol. The inhibitory effect on cell proliferation was assessed using the CCK?8 assay. Flow cytometry was employed to evaluate cell apoptosis and cycle distribution. Additionally, qRT?PCR and Western blotting techniques were utilized to analyze gene and protein expression levels. Results The proliferation of RPMI 8226 and ARH77 cells was dose? and time?dependently inhibited by 6?gingerol, leading to the induction of apoptosis with statistically significant differences (P < 0.05). Further mechanistic investigations revealed that treatment with 6?gingerol arrested RPMI 8226 cells in the G0/G1 phase, resulting in a significant increase in Bax levels and a decrease in Bcl?2 mRNA and c?Myc mRNA levels (P < 0.05). Additionally, it significantly upregulated the expression of Bax, Cleaved?PARP, Cleaved?caspase3, P53, and p?AKT proteins while down regulating the expression of Bcl?2 protein (P < 0.05). Conclusions The compound 6?Gingerol exhibits inhibitory effects on the proliferation and induction of apoptosis in MM cells, as well as cell cycle arrest at the G0/G1 phase. Its mechanism of action is likely associated with the suppression of the AKT signaling pathway, downregulation of Bcl?2 family protein expression, and inhibition of c?Myc expression.

Cite this article

Chunfang KONG , Anna LI , Bo KE , Weirong DING , Tingting LIU , Huan FU , Tingting ZHANG , Chenghao JIN , Mei. WU . The inhibitory effect and molecular mechanism of 6-gingerol on human multiple myeloma cells[J]. The Journal of Practical Medicine, 2024 , 40(23) : 3291 -3297 . DOI: 10.3969/j.issn.1006-5725.2024.23.003

References

1 FAZIO M, DEL FABRO V, PARRINELLO N L, et al. Multiple myeloma in 2023 ways: From trials to real life [J]. Curr Oncol, 2023, 30(11): 9710-9733. doi:10.3390/curroncol30110705
2 GARFALL A L. New biological therapies for multiple myeloma [J]. Annu Rev Med, 2024, 75: 13-29. doi:10.1146/annurev-med-050522-033815
3 SIEGEL R L, MILLER K D, FUCHS H E, et al. Cancer statistics, 2022 [J]. CA Cancer J Clin, 2022, 72(1): 7-33. doi:10.3322/caac.21708
4 WU S, ZHU J, WU G, et al. 6-Gingerol alleviates ferroptosis and inflammation of diabetic cardiomyopathy via the Nrf2/HO-1 Pathway [J]. Oxid Med Cell Longev, 2022, 2022: 3027514. doi:10.1155/2022/3027514
5 TSAI Y, XIA C, SUN Z. The Inhibitory effect of 6-Gingerol on ubiquitin-specific peptidase 14 enhances autophagy-dependent ferroptosis and anti-tumor in vivo and in vitro [J]. Front Pharmacol, 2020, 11: 598555. doi:10.3389/fphar.2020.598555
6 BHASKAR A, KUMARI A, SINGH M, et al. [6]-Gingerol exhibits potent anti-mycobacterial and immunomodulatory activity against tuberculosis [J]. Int Immunopharmacol, 2020, 87: 106809. doi:10.1016/j.intimp.2020.106809
7 HAN J J, LI X, YE Z Q, et al. Treatment with 6-Gingerol regulates dendritic cell activity and ameliorates the severity of experimental autoimmune encephalomyelitis [J]. Mol Nutr Food Res, 2019, 63(18): e1801356. doi:10.1002/mnfr.201801356
8 LI A, ZHAO M, YANG Z, et al. 6-Gingerol alleviates placental injury in preeclampsia by inhibiting oxidative stress via BNIP3/LC3 signaling-mediated trophoblast mitophagy [J]. Front Pharmacol, 2023, 14: 1243734. doi:10.3389/fphar.2023.1243734
9 GUNAWAN S, MUNIKA E, WULANDARI E T, et al. 6-gingerol ameliorates weight gain and insulin resistance in metabolic syndrome rats by regulating adipocytokines [J]. Saudi Pharm J, 2023, 31(3): 351-358. doi:10.1016/j.jsps.2023.01.003
10 KIM M J, KU J M, CHOI Y J, et al. Reduced HIF-1α Stability Induced by 6-Gingerol Inhibits Lung Cancer Growth through the Induction of Cell Death [J]. Molecules, 2022, 27(7): 2106. doi:10.3390/molecules27072106
11 ZHANG H, KIM E, YI J, et al. [6]-Gingerol Suppresses Oral Cancer Cell Growth by Inducing the Activation of AMPK and Suppressing the AKT/mTOR Signaling Pathway [J]. In Vivo, 2021, 35(6): 3193-3201. doi:10.21873/invivo.12614
12 CHOI N R, CHOI W G, KWON M J, et al. [6]-Gingerol induces Caspase-Dependent Apoptosis in Bladder Cancer cells via MAPK and ROS Signaling [J]. Int J Med Sci, 2022, 19(7): 1093-1102. doi:10.7150/ijms.73077
13 SALARI Z, KHOSRAVI A, POURKHANDANI E, et al. The inhibitory effect of 6-gingerol and cisplatin on ovarian cancer and antitumor activity: In silico, in vitro, and in vivo [J]. Front Oncol, 2023, 13: 1098429. doi:10.3389/fonc.2023.1098429
14 AL-ODAT O S, GUIRGUIS D A, SCHMALBACH N K, et al. Autophagy and apoptosis: current challenges of treatment and drug resistance in multiple myeloma [J]. Int J Mol Sci, 2022, 24(1): 644. doi:10.3390/ijms24010644
15 CZABOTAR P E, LESSENE G, STRASSER A, et al. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy [J]. Nat Rev Mol Cell Biol, 2014, 15(1): 49-63. doi:10.1038/nrm3722
16 LOPEZ J, TAIT S W. Mitochondrial apoptosis: killing cancer using the enemy within [J]. Br J Cancer, 2015, 112(6): 957-962. doi:10.1038/bjc.2015.85
17 DREL V R, SHYMANS'KY? I O, SYBIRNA N O, et al. Role of PARP and protein poly-ADP-ribosylation process in regulation of cell functions [J]. Ukr Biokhim Zh (1999), 2011, 83(6): 5-34.
18 ZHANG Y, YANG X, ZHOU H, et al. BIBR1532 inhibits proliferation and enhances apoptosis in multiple myeloma cells by reducing telomerase activity [J]. PeerJ, 2023, 11: e16404. doi:10.7717/peerj.16404
19 KERROS C, CAVEY T, SOLA B, et al. Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells [J]. J Exp Clin Cancer Res, 2009, 28(1): 77. doi:10.1186/1756-9966-28-77
20 SHEN W, ZHAO Y, CHEN H, et al. M3, a natural lignan xyloside, exhibits potent anticancer activity in HCT116 cells [J]. Oncol Lett, 2019, 17(2): 2117-2122.
21 ZHANG Y, QIAN J, JIANG M, et al. LTe2 induces cell apoptosis in multiple myeloma by suppressing AKT phosphorylation at Thr308 and Ser473 [J]. Front Oncol, 2023, 13: 1269670. doi:10.3389/fonc.2023.1269670
22 SAADOUNE C, NOUADI B, HAMDAOUI H, et al. Multiple Myeloma: Bioinformatic Analysis for Identification of Key Genes and Pathways [J]. Bioinform Biol Insights, 2022, 16: 11779322221115545. doi:10.1177/11779322221115545
23 ENGELAND K. Cell cycle regulation: p53-p21-RB signaling [J]. Cell Death Differ, 2022, 29(5): 946-960. doi:10.1038/s41418-022-00988-z
24 MASSó-VALLéS D, SOUCEK L. Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc [J]. Cells, 2020, 9(4): 883. doi:10.3390/cells9040883
25 ADIKESAVAN M, ATHIRAJA P, DIVAKAR M B B. Investigation on the anticancer activity of [6]-gingerol of zingiber officinale and its structural analogs against skin cancer [J]. Curr Comput Aided Drug Des, 2024, 20(4): 367-373. doi:10.2174/1573409919666230418095105
26 KHAN H, AZAD I, ARIF Z, et al. Structure based docking and biological evaluation towards exploring potential anti-cancerous and apoptotic activity of 6-Gingerol against human prostate carcinoma cells [J]. BMC Complement Med Ther, 2024, 24(1): 8. doi:10.1186/s12906-023-04269-1
27 LI B, ZU M, JIANG A, et al. Magnetic natural lipid nanoparticles for oral treatment of colorectal cancer through potentiated antitumor immunity and microbiota metabolite regulation [J]. Biomaterials, 2024, 307: 122530. doi:10.1016/j.biomaterials.2024.122530
28 EDIRIWEERA M K, TENNEKOON K H, SAMARAKOON S R. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance [J]. Semin Cancer Biol, 2019, 59: 147-160. doi:10.1016/j.semcancer.2019.05.012
29 ISA R, HORINAKA M, TSUKAMOTO T, et al. The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma [J]. Int J Mol Sci, 2022, 23(6): 2919. doi:10.3390/ijms23062919
30 LU Q, YANG D, LI H, et al. Multiple myeloma: signaling pathways and targeted therapy [J]. Mol Biomed, 2024, 5(1): 25. doi:10.1186/s43556-024-00188-w
31 XU S, ZHANG H, LIU T, et al. 6-Gingerol induces cell-cycle G1-phase arrest through AKT-GSK 3β-cyclin D1 pathway in renal-cell carcinoma [J]. Cancer Chemother Pharmacol, 2020, 85(2): 379-390. doi:10.1007/s00280-019-03999-9
Outlines

/