A Novel Hydroxamic Acid-Based Curcumin Derivative As Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma

Overview

Journal Front Oncol

Specialty Oncology

Date 2021 Nov 22

PMID 34804949

Citations 4

Authors

Hao Wang

Lei Shi

Zhimin Wang

Affiliations

Soon will be listed here.

Abstract

Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1-2 and HDAC6 with IC values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients.

Citing Articles

Curcumin Derivatives in Medicinal Chemistry: Potential Applications in Cancer Treatment.

Kuzminska J, Szyk P, Mlynarczyk D, Bakun P, Muszalska-Kolos I, Dettlaff K Molecules. 2024; 29(22).

PMID: 39598712 PMC: 11596437. DOI: 10.3390/molecules29225321.

Research Progress on the Mechanism of Histone Deacetylases in Ferroptosis of Glioma.

Ma M, Fei X, Jiang D, Chen H, Xie X, Wang Z Oncol Rev. 2024; 18:1432131.

PMID: 39193375 PMC: 11348391. DOI: 10.3389/or.2024.1432131.

Inhibitory effect of a novel Curcumin derivative DMC-HA on keloid fibroblasts.

Hu L, Bao Z Aging (Albany NY). 2024; 16(3):2398-2409.

PMID: 38284901 PMC: 10911336. DOI: 10.18632/aging.205487.

Inhibition of TGF-β1-induced epithelial-mesenchymal transition in gliomas by DMC-HA.

Shi L, Wang Z, Rong J, Fei X, Li X, He B Aging (Albany NY). 2023; 15(24):15183-15195.

PMID: 38154100 PMC: 10781457. DOI: 10.18632/aging.205340.

References

Batash R, Asna N, Schaffer P, Francis N, Schaffer M . Glioblastoma Multiforme, Diagnosis and Treatment; Recent Literature Review. Curr Med Chem. 2017; 24(27):3002-3009. DOI: 10.2174/0929867324666170516123206. View

Chen R, Zhang M, Zhou Y, Guo W, Yi M, Zhang Z . The application of histone deacetylases inhibitors in glioblastoma. J Exp Clin Cancer Res. 2020; 39(1):138. PMC: 7368699. DOI: 10.1186/s13046-020-01643-6. View

Uddin M, Al Mamun A, Alghamdi B, Tewari D, Jeandet P, Sarwar M . Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches. Semin Cancer Biol. 2020; 83:100-120. DOI: 10.1016/j.semcancer.2020.12.015. View

Tan A, Ashley D, Lopez G, Malinzak M, Friedman H, Khasraw M . Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020; 70(4):299-312. DOI: 10.3322/caac.21613. View

Yao H, Liu J, Xu S, Zhu Z, Xu J . The structural modification of natural products for novel drug discovery. Expert Opin Drug Discov. 2016; 12(2):121-140. DOI: 10.1080/17460441.2016.1272757. View

Urdiciain A, Erausquin E, Melendez B, Rey J, Idoate M, Castresana J . Tubastatin A, an inhibitor of HDAC6, enhances temozolomide‑induced apoptosis and reverses the malignant phenotype of glioblastoma cells. Int J Oncol. 2019; 54(5):1797-1808. DOI: 10.3892/ijo.2019.4739. View

Kotha R, Luthria D . Curcumin: Biological, Pharmaceutical, Nutraceutical, and Analytical Aspects. Molecules. 2019; 24(16). PMC: 6720683. DOI: 10.3390/molecules24162930. View

Al-Awadhi F, Salvador-Reyes L, Elsadek L, Ratnayake R, Chen Q, Luesch H . Largazole is a Brain-Penetrant Class I HDAC Inhibitor with Extended Applicability to Glioblastoma and CNS Diseases. ACS Chem Neurosci. 2020; 11(13):1937-1943. PMC: 7390227. DOI: 10.1021/acschemneuro.0c00093. View

Wang P, Wang Z, Liu J . Role of HDACs in normal and malignant hematopoiesis. Mol Cancer. 2020; 19(1):5. PMC: 6945581. DOI: 10.1186/s12943-019-1127-7. View

10.

Xia C, Tao Y, Li M, Che T, Qu J . Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review). Exp Ther Med. 2020; 20(4):2923-2940. PMC: 7444376. DOI: 10.3892/etm.2020.9073. View

11.

Galanis E, Anderson S, Miller C, Sarkaria J, Jaeckle K, Buckner J . Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: results of Alliance N0874/ABTC 02. Neuro Oncol. 2017; 20(4):546-556. PMC: 5909661. DOI: 10.1093/neuonc/nox161. View

12.

Zhang Y, Ishida C, Ishida W, Lo S, Zhao J, Shu C . Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma. Clin Cancer Res. 2018; 24(16):3941-3954. PMC: 6095717. DOI: 10.1158/1078-0432.CCR-18-0260. View

13.

Was H, Krol S, Rotili D, Mai A, Wojtas B, Kaminska B . Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells. Clin Epigenetics. 2019; 11(1):11. PMC: 6337817. DOI: 10.1186/s13148-018-0598-5. View

14.

Oberheim Bush N, Chang S, Berger M . Current and future strategies for treatment of glioma. Neurosurg Rev. 2016; 40(1):1-14. DOI: 10.1007/s10143-016-0709-8. View

15.

Shi L, Sun G, Zhang Y . Demethoxycurcumin analogue DMC-BH exhibits potent anticancer effects on orthotopic glioblastomas. Aging (Albany NY). 2020; 12(23):23795-23807. PMC: 7762498. DOI: 10.18632/aging.103981. View

16.

Witt O, Deubzer H, Milde T, Oehme I . HDAC family: What are the cancer relevant targets?. Cancer Lett. 2008; 277(1):8-21. DOI: 10.1016/j.canlet.2008.08.016. View

17.

Touat M, Idbaih A, Sanson M, Ligon K . Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol. 2017; 28(7):1457-1472. PMC: 5834086. DOI: 10.1093/annonc/mdx106. View

18.

Hegi M, Diserens A, Gorlia T, Hamou M, De Tribolet N, Weller M . MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005; 352(10):997-1003. DOI: 10.1056/NEJMoa043331. View

19.

Leng L, Zhong X, Sun G, Qiu W, Shi L . Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo. Tumour Biol. 2016; 37:15847–15857. DOI: 10.1007/s13277-016-5399-x. View

20.

Lee E, Reardon D, Schiff D, Drappatz J, Muzikansky A, Grimm S . Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. Neuro Oncol. 2015; 17(6):862-7. PMC: 4483124. DOI: 10.1093/neuonc/nou350. View