KML001, a Telomere-Targeting Drug, Sensitizes Glioblastoma Cells to Temozolomide Chemotherapy and Radiotherapy through DNA Damage and Apoptosis

Woo, Seon Rang; Ham, Yunhee; Kang, Wonyoung; Yang, Heekyoung; Kim, Sujong; Jin, Juyoun; Joo, Kyeung Min; Nam, Do‐Hyun

doi:10.1155/2014/747415

Cited by 22 publications

(16 citation statements)

References 30 publications

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“…Previous studies have demonstrated that antileukemia activity of KML001 is mainly due to its ability to induce apoptosis and cell cycle arrest via regulation of MAPK and PI3K pathways or telomere shortening (6,24). Also, our study showed that KML001 induced apoptosis both in CCRF-CEM and Molt-4 cell lines.…”

Section: Discussionsupporting

confidence: 69%

KML001 and doxercalciferol induce synergistic antileukemic effect in acute lymphoid leukemia cells

Liu

Shin

et al. 2017

Oncology Reports

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KML001 (NaAsO2, sodium metaarsenite, KOMINOX), a kind of arsenic compound, that has shown promising efficacy in non-Hodgkin's lymphoma (NHL) both in vitro and in vivo. In our study, the antileukemic effect of KML001 on acute lymphoid leukemia (ALL) and its mechanism of action were investigated. The results showed that KML001 inhibited cell proliferation in two types of ALL cell lines, CCRF-CEM and Molt-4. Exposure of ALL cells to KML001 induced apoptosis in a time-dependent manner. KML001 caused cell cycle arrest at G2/M phase instead of G0/G1 phase shown in other leukemia cells. In addition, we also tested the possibility of synergy of KML001 with doxercalciferol, a vitamin D2 derivative. Also, we found that a combination of KML001 with doxercalciferol showed a synergistic effect on ALL cell lines and this could be due to its different mechanism of action. Overall, our findings demonstrated KML001 could be a promising antileukemic agent especially when it is combined with doxercalciferol in ALL treatment.

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Section: Discussionsupporting

confidence: 69%

KML001 and doxercalciferol induce synergistic antileukemic effect in acute lymphoid leukemia cells

Liu

Shin

et al. 2017

Oncology Reports

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“…To overcome the barrier, current studies concentrate on combinations with other agents and on development of novel molecular targeting agents . Recently, improvement of TMZ resistance on GMB was reported largely . For example, a varies of microRNAs and agents were found to enhance the sensitivity of GBM to TMZ .…”

Section: Discussionmentioning

confidence: 99%

MCCK1 enhances the anticancer effect of temozolomide in attenuating the invasion, migration and epithelial‐mesenchymal transition of glioblastoma cells in vitro and in vivo

Liu

et al. 2019

Cancer Medicine

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Chemotherapy with temozolomide (TMZ) is the traditional treatment for glioblastoma (GBM). Nevertheless, majority of GBM patients have recurrence from resistance to the chemotherapy. Herein, we examined combinational effects of MCCK1 (a specific and effective IKKε inhibitor) with TMZ in GBM U251MG and U‐87MG cell lines as well as U251MG xenograft models to overcome the therapeutic limitation of chemotherapy for GBM. Although MCCK1 alone showed inhibitory effects on in vitro proliferation, migration, invasion, and EMT of U251MG and U‐87MG cells, combination of MCCK1 and TMZ showed enhanced inhibitory effects. In the U251MG GBM xenograft models, MCCK1 showed synergistic therapeutic effects in combination with TMZ to reduce tumor volumes significantly. These data indicated that MCCK1 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for GBM.

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“…This improved effect resulted marginally synergistic. Since IDE appears to enhance the cytotoxic effects of TMZ, this novel combination for GB therapy merits further investigation, especially as combinations of other drugs and natural compounds with TMZ are being explored continuously (27,31,(35)(36)(37)(38)(39)(40). OX has been occasionally used for treating GB but limited due to its side effects (41).…”

Section: Discussionmentioning

confidence: 99%

Repurposing of idebenone as a potential anti-cancer agent

Damiani

Wallace

2019

Biochemical Journal

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Glioblastoma (GB) represents the most common and aggressive form of malignant primary brain tumour associated with high rates of morbidity and mortality. In the present study, we considered the potential use of idebenone (IDE), a Coenzyme Q10 analogue, as a novel chemotherapeutic agent for GB. On two GB cell lines, U373MG and U87MG, IDE decreased the viable cell number and enhanced the cytotoxic effects of two known anti-proliferative agents: temozolomide and oxaliplatin. IDE also affected the clonogenic and migratory capacity of both GB cell lines, at 25 and 50 µM, a concentration equivalent to that transiently reached in plasma after oral intake that is deemed safe for humans. p21 protein expression was decreased in both cell lines, indicating that IDE likely exerts its effects through cell cycle dysregulation, and this was confirmed in U373MG cells only by flow cytometric cell cycle analysis which showed S-phase arrest. Caspase-3 protein expression was also significantly decreased in U373MG cells indicating IDE-induced apoptosis that was confirmed by flow cytometric Annexin V/propidium iodide staining. No major decrease in caspase-3 expression was observed in U87MG cells nor apoptosis as observed by flow cytometry analysis. Overall, the present study demonstrates that IDE has potential as an anti-proliferative agent for GB by interfering with several features of glioma pathogenesis such as proliferation and migration, and hence might be a drug that could be repurposed for aiding cancer treatments. Furthermore, the synergistic combinations of IDE with other agents aimed at different pathways involved in this type of cancer are promising.

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KML001, a Telomere-Targeting Drug, Sensitizes Glioblastoma Cells to Temozolomide Chemotherapy and Radiotherapy through DNA Damage and Apoptosis

Cited by 22 publications

References 30 publications

KML001 and doxercalciferol induce synergistic antileukemic effect in acute lymphoid leukemia cells

KML001 and doxercalciferol induce synergistic antileukemic effect in acute lymphoid leukemia cells

MCCK1 enhances the anticancer effect of temozolomide in attenuating the invasion, migration and epithelial‐mesenchymal transition of glioblastoma cells in vitro and in vivo

Repurposing of idebenone as a potential anti-cancer agent

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