Synergistic Anticancer Effects of Formononetin and Temozolomide on Glioma C6 Cells

Zhang, Xiong; Ni, Qi; Wang, Ying; Fan, Hongwei; Li, Yingbin

doi:10.1248/bpb.b18-00002

Cited by 39 publications

(25 citation statements)

References 29 publications

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“…Our results demonstrated that intrinsic or mitochondrial pathway is involved in the induction of apoptosis after TMZ treatment in RH30 cells (significant increase in caspase-9 activation) while TMZ-induced apoptosis is not caspase-9 dependent in C2C12 cells. It has been reported that TMZ-induced apoptosis is caspase dependent in different models, including glioma cells 68 – 70 , and human glioma stem cells 71 . It has been previously reported that TMZ induces endoplasmic reticulum (ER)-stress with subsequent unfolded protein response in many cell models.…”

Section: Discussionmentioning

confidence: 99%

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

et al. 2018

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Rhabdomyosarcoma (RMS) is a muscle-derived tumor. In both pre-clinical and clinical studies Temozolomide (TMZ) has been recently tested against RMS; however, the precise mechanism of action of TMZ in RMS remains unclear. Here we demonstrate that TMZ decreases the cell viability of the RH30 RMS and C2C12 cell line, where cells display evidence of mitochondrial outer membrane permeability. Interestingly, the C2C12 mouse myoblast line was relatively more resistant to TMZ-induced apoptosis. Moreover, we observed that TMZ activated biochemical and morphological markers of autophagy in both cell lines. Autophagy inhibition in both RH30 and C2C12 cells significantly increased TMZ-induced cell death. In RH30 cells, TMZ increased Mcl-1 and Bax protein expression compared to corresponding time match controls while in C2C12 Mcl-1, Bcl-2, Bcl-XL, and Bax protein expression were not changed. Baf-A1 co-treatment with TMZ significantly decrease Mcl-1 expression compared to TMZ while increase Bax expression in C2C12 cells (Bcl2 and Bcl-XL do not significantly change in Baf-A1/TMZ co-treatment). Using a three-dimensional (3D) C2C12 and RH30 culture model we demonstrated that TMZ is significantly more toxic in RH30 cells (live/dead assay). Additionally, we have observed in our 3D culture model that TMZ induced both apoptosis (cleavage of PARP) and autophagy (LC3-puncta and localization of LC3/p62). Therefore, our data demonstrate that TMZ induces simultaneous autophagy and apoptosis in both RH30 and C2C12 cells in 2D and 3D culture model, where RH30 cells are more sensitive to TMZ-induced death. Furthermore, autophagy serves to protect RH30 cells from TMZ-induced death.

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Section: Discussionmentioning

confidence: 99%

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

et al. 2018

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“…In addition to that, formononetin also worked synergistically with temozolomide against glioma C6 cells. The combination of formononetin with temozolomide enhanced apoptosis and inhibited migration of glioma cells (Zhang et al, 2018b).…”

Section: Combinatorial Use Of Formononetin With Other Chemotherapeutimentioning

confidence: 99%

Formononetin: A Review of Its Anticancer Potentials and Mechanisms

et al. 2019

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Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C 16 H 12 O 4 ), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus . The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

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“…Isoflavones, like formononetin, has increased benefits with fewer side effects when used as a combination drug with chemotherapy or as a postoperative adjuvant therapy 46 , 47 . We also found that MEQ displayed few adverse effects in mice, suggesting that MEQ may have clinical applications in combination with other chemotherapeutic drugs in TNBC treatment.…”

Section: Discussionmentioning

confidence: 99%

An isoflavone derivative potently inhibits the angiogenesis and progression of triple-negative breast cancer by targeting the MTA2/SerRS/VEGFA pathway

Zhang

Zou

et al. 2020

Cancer Biol. Med.

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Synergistic Anticancer Effects of Formononetin and Temozolomide on Glioma C6 Cells

Cited by 39 publications

References 29 publications

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

Autophagy modulates temozolomide-induced cell death in alveolar Rhabdomyosarcoma cells

Formononetin: A Review of Its Anticancer Potentials and Mechanisms

An isoflavone derivative potently inhibits the angiogenesis and progression of triple-negative breast cancer by targeting the MTA2/SerRS/VEGFA pathway

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