Lumefantrine, an Antimalarial Drug, Reverses Radiation and Temozolomide Resistance in Glioblastoma

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 May 16

PMID 32409605

Citations 18

Authors

Yetirajam Rajesh

Angana Biswas

Utkarsh Kumar

Indranil Banerjee

Subhayan Das

Santanu Maji

Swadesh K Das

Luni Emdad

Webster K Cavenee

Mahitosh Mandal

Paul B Fisher

Affiliations

Soon will be listed here.

Abstract

Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.

Citing Articles

FLI-1-driven regulation of endothelial cells in human diseases.

Zhang L, Ge T, Cui J J Transl Med. 2024; 22(1):740.

PMID: 39107790 PMC: 11302838. DOI: 10.1186/s12967-024-05546-4.

Overcoming Resistance to Temozolomide in Glioblastoma: A Scoping Review of Preclinical and Clinical Data.

Smerdi D, Moutafi M, Kotsantis I, Stavrinou L, Psyrri A Life (Basel). 2024; 14(6).

PMID: 38929657 PMC: 11204771. DOI: 10.3390/life14060673.

RPL22L1, a novel candidate oncogene promotes temozolomide resistance by activating STAT3 in glioblastoma.

Chen Y, Mu Y, Guan Q, Li C, Zhang Y, Xu Y Cell Death Dis. 2023; 14(11):757.

PMID: 37985768 PMC: 10662465. DOI: 10.1038/s41419-023-06156-6.

Mechanistic insights into super-enhancer-driven genes as prognostic signatures in patients with glioblastoma.

Chen Y, Pan Y, Gao H, Yi Y, Qin S, Ma F J Cancer Res Clin Oncol. 2023; 149(13):12315-12332.

PMID: 37432454 DOI: 10.1007/s00432-023-05121-2.

Deciphering glioma epitranscriptome: focus on RNA modifications.

Piperi C, Markouli M, Gargalionis A, Papavassiliou K, Papavassiliou A Oncogene. 2023; 42(28):2197-2206.

PMID: 37322070 DOI: 10.1038/s41388-023-02746-y.

References

Das S, Sarkar D, Emdad L, Fisher P . MDA-9/Syntenin: An emerging global molecular target regulating cancer invasion and metastasis. Adv Cancer Res. 2019; 144:137-191. DOI: 10.1016/bs.acr.2019.03.011. View

Byakika-Kibwika P, Lamorde M, Mayanja-Kizza H, Khoo S, Merry C, Van Geertruyden J . Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals. Malar Res Treat. 2012; 2011:703730. PMC: 3265289. DOI: 10.4061/2011/703730. View

Rajesh Y, Biswas A, Mandal M . Glioma progression through the prism of heat shock protein mediated extracellular matrix remodeling and epithelial to mesenchymal transition. Exp Cell Res. 2017; 359(2):299-311. DOI: 10.1016/j.yexcr.2017.08.032. View

Liu H, Wang L, Lv M, Pei R, Li P, Pei Z . AlzPlatform: an Alzheimer's disease domain-specific chemogenomics knowledgebase for polypharmacology and target identification research. J Chem Inf Model. 2014; 54(4):1050-60. PMC: 4010297. DOI: 10.1021/ci500004h. View

Kegelman T, Das S, Hu B, Bacolod M, Fuller C, Menezes M . MDA-9/syntenin is a key regulator of glioma pathogenesis. Neuro Oncol. 2013; 16(1):50-61. PMC: 3870820. DOI: 10.1093/neuonc/not157. View

Torlakovic E, Slipicevic A, Florenes V, Chibbar R, DeCoteau J, Bilalovic N . Fli-1 expression in malignant melanoma. Histol Histopathol. 2008; 23(11):1309-14. DOI: 10.14670/HH-23.1309. View

Song W, Zhang T, Li W, Mu R, Zhang L, Li Y . Overexpression of Fli-1 is associated with adverse prognosis of endometrial cancer. Cancer Invest. 2015; 33(9):469-75. DOI: 10.3109/07357907.2015.1069831. View

Ben-David Y, Giddens E, Letwin K, Bernstein A . Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev. 1991; 5(6):908-18. DOI: 10.1101/gad.5.6.908. View

Das S, Sarkar D, Cavenee W, Emdad L, Fisher P . Rethinking Glioblastoma Therapy: MDA-9/Syntenin Targeted Small Molecule. ACS Chem Neurosci. 2019; 10(3):1121-1123. DOI: 10.1021/acschemneuro.9b00016. View

10.

Dey G, Bharti R, Ojha P, Pal I, Rajesh Y, Banerjee I . Therapeutic implication of 'Iturin A' for targeting MD-2/TLR4 complex to overcome angiogenesis and invasion. Cell Signal. 2017; 35:24-36. DOI: 10.1016/j.cellsig.2017.03.017. View

11.

Oikawa T, Yamada T . Molecular biology of the Ets family of transcription factors. Gene. 2003; 303:11-34. DOI: 10.1016/s0378-1119(02)01156-3. View

12.

Yang C, Hong C, Zhuang Z . Hypoxia and glioblastoma therapy. Aging (Albany NY). 2015; 7(8):523-4. PMC: 4586094. DOI: 10.18632/aging.100795. View

13.

Bharti R, Dey G, Ojha P, Rajput S, Jaganathan S, Sen R . Diacerein-mediated inhibition of IL-6/IL-6R signaling induces apoptotic effects on breast cancer. Oncogene. 2015; 35(30):3965-75. DOI: 10.1038/onc.2015.466. View

14.

Liu F, Walmsley M, Rodaway A, Patient R . Fli1 acts at the top of the transcriptional network driving blood and endothelial development. Curr Biol. 2008; 18(16):1234-40. DOI: 10.1016/j.cub.2008.07.048. View

15.

Oikawa T . ETS transcription factors: possible targets for cancer therapy. Cancer Sci. 2004; 95(8):626-33. PMC: 11159856. DOI: 10.1111/j.1349-7006.2004.tb03320.x. View

16.

Hammerer-Lercher A, Mair J, Bonatti J, Watzka S, Puschendorf B, Dirnhofer S . Hypoxia induces heat shock protein expression in human coronary artery bypass grafts. Cardiovasc Res. 2001; 50(1):115-24. DOI: 10.1016/s0008-6363(01)00198-5. View

17.

Scheiber M, Watson P, Rumboldt T, Stanley C, Wilson R, Findlay V . FLI1 expression is correlated with breast cancer cellular growth, migration, and invasion and altered gene expression. Neoplasia. 2014; 16(10):801-13. PMC: 4212256. DOI: 10.1016/j.neo.2014.08.007. View

18.

Liang X, Shi D, Yun J, Mao Y, Ouyang P, Su Z . Friend leukemia virus integration 1 expression has prognostic significance in nasopharyngeal carcinoma. Transl Oncol. 2014; 7(4):493-502. PMC: 4202802. DOI: 10.1016/j.tranon.2014.04.015. View

19.

Parida S, Maiti C, Rajesh Y, Dey K, Pal I, Parekh A . Gold nanorod embedded reduction responsive block copolymer micelle-triggered drug delivery combined with photothermal ablation for targeted cancer therapy. Biochim Biophys Acta Gen Subj. 2016; 1861(1 Pt A):3039-3052. DOI: 10.1016/j.bbagen.2016.10.004. View

20.

Davidson B, Reich R, Goldberg I, Gotlieb W, Kopolovic J, Berner A . Ets-1 messenger RNA expression is a novel marker of poor survival in ovarian carcinoma. Clin Cancer Res. 2001; 7(3):551-7. View