Valproic Acid가 사춘기 여아의 난소에 미치는 영향

문은경(Eun Kyoung Moon),임혜경(Hae Kyung Lim),유재홍(Jea Hong Yoo),이건수 (Keon Su Lee) 대한소아신경학회 2001 대한소아신경학회지 Vol.9 No.1

목적: Valproic acid는 소아와 성인 모두에게서 광범위하게 쓰이며, 전신 발작과 부분 발작 등 여러 종류의 경련에 치료 효과와 안전성이 입증된 항경련제이다. 지금까지 보고된 흔한 위장관계의 부작용과 체중 증가, 간독성, 그리고 드물게는 신경계 부작용 외에, 여성에서 특히 20세 이전부터 valproic acid를 복용한 경우 안드로젠과잉증과 다낭성 난포 등의 발생이 보고되고 있다. 이에 저자는 valproic acid가 소아와 청소년기의 여아들에서 생식 내분비계에 미치는 영향에 대해 알아보기 위해, valproic acid를 복용 중인 다양한 시기의 사춘기 여아를 대상으로 체형, 난소의 형태 및 성호르몬에 대한 연구를 실시하였다. 방법: 2000년 1월부터 7월까지 충남대학교병원 소아과에서 간질로 진단받고 valproic acid를 복용하고 있는 환아 중 8세에서 18세까지의 여아 23례를 대상으로, 경련의 형태와 투여된 valproic acid의 용량과 기간을 조사 후, 신장과 체중을 측정하여 Body Mass Index를 산출하였다. 사춘기의 단계는 Tanner stage에 따라 결정하였고, 초음파로 직장을 통하여 난소 여포를 관찰하여 다낭성 난포를 진단하였다. 혈중 성호르몬의 농도 측정은 채혈을 통하여 free testosterone, sex hormone-binding globulin(SHBG), luteinizing hormone(LH), follicle-stimulating hormone(FSH), estradiol 등을 측정하였다. 결과: Valproic acid를 투여 중인 간질 환아 23명 중 5명은 사춘기 전기였으며, 13명은 사춘기였고, 5명은 사춘기 후기에 해당하였으며, 이중 비만에 속하는 환아는 2명이었다. 평균 혈청 SHBG, LH, FSH, estradiol의 혈중 농도는 기준치와 비교시, 사춘기전기, 사춘기, 사춘기후기 모두에서 정상에 속하였다. 규칙적인 월경 주기를 갖는 정상 여아에서의 다낭성 난포의 발생율이 9%인데 비해, 본 연구에서는 valproic acid를 복용중인 20명의 여아 중 다낭성 난포의 발생은 5명으로 25%에 해당하였다. 결론: Valproic acid를 투여 중인 여아에서 규칙적인 난소의 초음파 검사는 필요한 것으로 사료된다. 하지만, 난소의 형태학적 변화가 valproic acid에 의해서 유발되는 지의 여부를 결정하기 위해서는 더 깊은 연구가 필요할 것으로 사료된다. Purpose: Valproic acid is effective and safe in adults and children for the treatment of a variety of seizure types. But, according to the recent reports, this drug induce hyperandrogenism, obesity, and polycystic ovaries, particularly when the medication is stared before the age of 20. This research was designed to study the effect of valproic acid on ovary of pubertal child. Methods: The sample group consisted of 23 girls who were diagnosed to epilepsy by our department of pediatrics, and were taking valproic acid from January 2000 to July 2000. They were evaluated reproductive endocrine function with the serum sex hormones and ultrasonographic study of ovary. Results: 1) The mean serum sex hormones concentration of prepubertal, pubertal, and postpubertal girls taking valproic acid were belong to the normal range of reference values of textbook of Nelson and Park's report. 2) The obesity were seen in two of the 23 girls taking valproic acid. 3) The rate of polycystic ovaries in normal girls with regular menstruation has been reported in 9%, but, in our report, polycystic ovaries were seen in five of the 20 girls taking valproic acid(25%). Conclusion: Ultrasinographic study of ovaries is required for the girls taking valproic acid. If the problems from the polycystic ovary are developed on patients taking valproic acid, the substitution of other anticonvulsant drug for valproic acid may be required. However, further study was needed to clarify whether this ovarian morphologic changes were elicited by valproic acid or not.

초기계태에서 valproic acid에 의한 신경관 기형 : 입체현미경적 관찰

김동호,조무연,정유남,최영주,이종선,민경수,이무섭 충북대학교 의학연구소 2000 忠北醫大學術誌 Vol.10 No.1

연구목적 ' 항경련제인 valproic acid가 초기계태의 신경관 형성에 영향을 주는 기형유발에 대해 입체현미경하에서 관찰하였다 연구재 료 및 방법 : 백색의 Leghorn의 신선한 수정란을 30-35시간 동안 배양하여 Hamburger & Hamilton 기 5-10기의 초기 계태를 천공 필터를 이용하여 분리하여 6-30시간 동안 CO2 세포 배양기에서 배양하였고 무작위로 대조군과 실험군을 분류하였다. 실험군은 valproic acid 의 RPMI culture media 의 농도에 따라 100 ㎍/㎖, 200 ㎍/㎖, 500 ㎍/㎖, 1000 ㎍/㎖ 네가지 군으로 분리하였다. 각각의 대조군과 valproic acid를 처치한 실험군에서 입체 현미경하에서 초기계태의 신경관 형성의 형태학적인 특징과 기형형성의 빈도를 비교하였다. 결과: valproic acid가 없는 RPMI media에서 배양된 대조군은 24개의 계태는 22(91.7%)개는 정상으로 자랐으며 2(8.3%)개는 비정상으로 자랐다 이에 반하여 valproic acid가 처치된 RPMI media에서 배양된 72개의 계태는 42(58.3%)개가 비정상으로 자랐다. 주로 확인된 이상 형태는 신경주름의 변형. 신경관 폐쇄부전, 체절의 장애 및 발육 정지 등 이었다. 계태의 기형 형성은 valproic acid의 농도에 비례하여 증가하였다. valproic acrid 의 농도가 100 ㎍/㎖인 경우 18개 계태 중 2(11.1%)개에서 경미한 신경관 기형이 나타났으며 200 ㎍/㎖인 경우 18개 계태 중 11(61,1%)개는 정상, 7(38.9%)개는 명백한 신경관 기형이 나타났으며 500 ㎍/㎖인 경우 18개의 계태 중 5(27.8%)개는 정상. 13(72.2%)개는 명백한 신경관 기형을 나타냈다. 1000 ㎍/㎖인 경우 18(100%)개 모두 심한 신경관 기형이 나타났다. 결론: valproic acid는 초기계태에서 신경관 기형을 유발 했는데 저농도에서는 일부 경미한 신경관 이상을 보였고 고농도에서는 대부분 심한 신경관 손상을 동반하고 성장 속도가 둔화되어 약 용량의 증가에 따라 기형이 증가되는 dose-dependent manner 로 그 영향이 나타났다. Purpose : The teratogeruc effects of valproic acid widely used as anticonvulsant on the neurulation of the explanted eraly chick embryos were observed by the stereoscope. Materials and Methods: Fresh fertilized white leghorn hen eggs were incubated for 30-35 hours in an e99 incubator. The Hamburger and Hamilton stage 5-10 chick embryos were explanted using the punched-out filter paper explantation technique and cultured in the CO2 cell culture incubator for 6-30 hours. They were randomly divided into a control group and an experimental group. The experimental group was divided into four subgroups according to the valproic acid concentrations of 100 ㎍/㎖, 200 ㎍/㎖, 500 ㎍/㎖, 1000 ㎍/㎖ with which the RPMI culture media were treated. The morphological characteristics and the incidences of teratogenic effects on the neurulation of early chick embryos in the control and experimental groups were compared with each other using the stereomicroscope. Results : Of the 24 chick embryos cultured in the RPMI media without valproic acrid, 22 embryos(91.7%) developed normally, and 2 embryos (8.3%) developed abnormally, in contrast, among 72 embryos cultured in the valproic acrid-treated media, 42 embryos(58.3%) developed abnormally. The frequent anomalous features were deformities of the neural folds, failure of neural tube closure, derangement of somites, and developmental arrest. Of 18 embryos cultured in the media treated each with 100㎍/㎖ of valproic acid, 2 embryos(11.1%) showed mild abnormality of neural tube defect on stereoscopic examination. Of 18 embryos cultured 7l the media treated each with 200㎍/㎖ of valproic acid, 11 embryos(61.1%) developed normally for 20 hours and 7 embryos (38.9%) showed definite neural tube defect. Of 18 embryos cultured in the media 7reated each with 500㎍/㎖ of vaIprolc acid, 5 embryos(27.8%) developed normally (or 20 hours and 13 embryos (72.2% ) showed definite neural tube defect. Of 18 embryos cultured in the media treated each with 1000㎍/㎖ of valproic acid, 1 embryo developed normally for 4 hours but all embryos (100%) showed severe neural tube defect on whole brain after 8 hours of culture. Conclusion : Valproic acid induced mild neural tube defects in low concentration and in high concentration of valproic acid, most chick embryos developed slowly and showed severe neral tube defects. The frequency and severity of abnormal embryos ulcreased in dose-dependent manner.

Meropenem 동시 사용으로 인한 Valproic acid의 혈중농도 감소 3예

노은경,김혜경,이명진,안보숙,송영구,김정호 대한화학요법학회 2002 대한화학요법학회지 Vol.20 No.4

서울에 위치한 일개 대학병원에서 광범위 항생제인 meropenem을 사용하기 시작한 2000년 4월부터 2001년 5월까지, valproic acid의 약동학 서비스가 의뢰된 432건 중 meropenem을 동시에 사용했던 3명의 환자에서 모두 valproic acid의 현저한 혈중농도저하를 관찰하였다. 이 급격한 혈중농도 변화기간에 3명의 환자에서 valporic acid와 동시에 사용된 공통 약물은 meropenem 뿐이었다. Meropenem을 사용하기 시작한 시점에서 7일 전후로 valproic acid의 혈중농도는 측정 한계치인 15㎍/㎖ 전후의 수준으로 급격히 감소되었으며, meropenem을 중단한지 1-2일 이내에 valproic acid의 농도는 meropenem을 사용하기 이전 수준으로 빠르게 회복되었다. 이들 환자중 1명은 meropenem을 사용하는 동안 발작을 경험하였다. Meropenem이 valproic acid의 혈중 농도를 감소시키는 기전은 아직 명확하지 않으나, 이들 두 약제의 동시 투여가 요구되는 상황에서는 valproic acid의 혈중농도 모니터링이 더 자주 필요하며, 가능한 다른 항경련제로의 일시적 교체를 고려하여야 할 것이다. Meropenem, a carbapenemn, has a broad spectrum of activity that includes β-lactamase-producing organisms, and are used frequently in treating various infections. Compared with imipenem/cilastatin, meropenem has a lower affinity for the γ-butyric acid (GABA) receptor and thus a lower potential for inducing seizures. This makes meropenern, even at higher dosages and costs, suitable for the treatment of patients with infections of the central nervous system and for the treatment of infections in patients with high risk of seizure attack. In 3 neurosurgical patients using valproic acid to control seizure, however, we experienced significant decrease of serum valproic acid concentration during concomitant use of meropenem. We report here our observations of decreases in the serum concentrations of valproic acid to sub-therapeutic levels in three adult neurosurgical patients during concomitant therapy with meropenem.

Valproic acid inhibits cell size and cell proliferation by AMPK-mediated mTOR signaling pathway in JEG-3 cells

김연정,한태준,송미경,이지나,류재춘 한국바이오칩학회 2013 BioChip Journal Vol.7 No.3

Valproic acid is commonly used to treat seizure disorders, bipolar disorder, migraine prophylaxis, and neuropathic pain. Despite its effectiveness and widespread use, valproic acid has been proven to exert considerable teratogenic potential, such as neural tube defects and malformations of the heart in both the humans and animals. However, the molecular mechanism of the teratogenic effects of valproic acid has not been fully elucidated. Because adverse effects in fetus by teratogens are obviously detectable only after birth and there are the limits of teratogenicity testing using rodents, such as thalidomide tragedy, new strategies for pre-determining teratogenic effects are required. Here, we try to elucidate the indirect teratogenicity of valproic acid in a human placenta-derived cell line (JEG-3) using a transcriptomic approach. In this study, using human whole genome oligonucleotide microarray, we identified 2,076 up- and 1,730 down-regulated genes which were changed more than 1.5-fold in JEG-3 cells exposed to valproic acid. Many of these genes have associations with lysosome, transport, tight junction, splicesome, cell cycle and mammalian target of rapamycin (mTOR)-signaling pathway. Among these, we focused on the adenosine monophosphate (AMP)- dependent kinase or AMP-activated kinase (AMPK)-mediated mTOR signaling pathway, and hypothesized that the negative control of mTOR signaling by AMPK might induce inhibition of the growth of JEG-3 cell exposed to valproic acid. First, flow cytometry analysis showed that valproic acid induced the inhibition of cell growth caused by G1 phase arrest. Second, the expression of genes related to mTOR signaling was changed. Using quantitative real-time RT-PCR data, it was confirmed that PTEN, PIK3CB, PIK3CD, PIK3R3, IRS2, and PRKAA2 (AMPKα2) were overexpressed, and that GβL and AKT1 were under-expressed in valproic acid treated JEG-3 cells compared to a control. We also confirmed the protein expression and the activation of AMPK and raptor after valproic acid exposure. Thus, this study suggests that valproic acid affects AMPK, and then AMPK may influence cell growth through mTOR signaling, and particularly, mTOR activity is suppressed by raptor activation. From this point of view, these genes may provide potential biomarkers that may contribute to decrease the number of candidate drugs showing teratogenicity in large-scale tests using placenta cells.

Carbamazepine과 Valproic Acid가 소아의 면역 상태에 미치는 영향

임병영(Byoung Young Lim),채수안(Soo Ahn Chae),유병훈(Byoung Hoon Yoo) 대한소아신경학회 1999 대한소아신경학회지 Vol.6 No.2

목 적 :소아에서 흔히 사용하고 있는 항경련제인 valproic acid와 carbamazepine은 혈액과 림프조직을 비롯한 여러 기관에 부작용을 초래할 수 있는 것으로 알려져 왔다. 그러나 이들 약제를 소아에서 장기간 복용시 발생할 수 있는 영향 중 소아의 면역 기능에 미치는 연구는 미미한 실정이다. 또한 지금까지 시행되었던 간질 환자를 대상으로 한 면역 상태에 관한 연구들은 다양한 연령층을 대상으로 하여 면역글로불린 변화 판정에 어려움이 있었다. 본 연구는 대상 연령을 소아 연령에 국한하여 연령으로 인한 면역 글로불린의 변이를 최소화하고, 더불어 소아 연령군의 항경련제 투여로 인한 면역글로불린의 변화를 알아보고자 이 연구를 시도하였다. 방 법 : 1997년 1월부터 1998년 6월까지 복합열성 경련 및 소아 간질로 valproic acid와 carbamazepine을 복용하고 있는 환아 30명(남자 16명, 여자 14명)을 대상으로 하였으며 치료전과 치료 10개월 후의 혈청 IgA, IgM, IgG의 변화를 비교하였다. Paired t-test를 이용하여 비교 검정하였고 면역글로불린의 변화를 p-value가 0.05 이하일 때 통계적으로 유의 하다고 판단하였다. 결 과 : 항경련제(valproic acid, carbamazepine)를 복용하고 있는 환자에서 항경련제 투여 전과 투여 10개월 후에 나타나는 혈청 면역글로블린의 변화는 다음과 같았다. 1) Valproic acid 투여 후 혈청 면역글로블린의 변화 투여 전 혈청 IgG 수치가 10.71± 3.34g/L에서 투여 10개월 후 13.36±5.36g/L으로 정상범위내에서 의미 있게 상승하였고 (p<0.05) IgA 및 IgM의 큰 변화는 없었다. 2) Carbamazepine 투여 후 혈청 면역글로블린의 변화 : 투여 전 혈청 IgG 수치가 8.42± 2.08g/L에서 투여 10개월 후 11.49±3.13g/L로 정상 범위내에서 상승을 보였고(p<0.05) IgA 및 IgM의 큰 변화는 없었다. 3) Valproic acid와 carbamazepine 병용 투여 후 혈청 면역글로블린의 변화 : 혈청 IgG 수치가 투여 전 7.64±0.99g/L에서 투여 10개월 후 10.36±1.58g/L로 valproic acid와 carbamazepine 단독 투여한 경우보다 IgG의 상승 폭이 더 컸으나 정상범위 내에서 증가하였다. IgA 및 IgM의 큰 차이는 나타나지 않았다. 결 론 : 본 연구 결과는 소아 간질 환자에서 valproic acid와 carbamazepine을 장기간 투여하였을 때 혈청 IgG가 증가하는 소견을 보였으며 혈청 IgG 증가는 소아 간질 환자 치료에 있어 항경련제 자체의 항경련 효과 외에 면역 기능의 변화로 인한 간질 치료 효과를 생각해 볼 수 있을 것이다. Purpose : Antiepileptic drug(AED) therapy has been reported to induce immunological alterations in epileptic patients. However, despite extensive studies, the accumulated data are not consistent and there is still confusion and controversy over the effects of AEDs on the immune system. This study tries to elucidate the effects of anticonvulsant on some immune parameters, and serum concentration of IgA, IgG, IgM. Methods : Thirty pediatric epileptic patients[Group A(n=12) : patients on carbamazepine, Group B(n=10) : patients on valproic acid and Group C(n=8) : patients on carbamazepine and valproic acid] were enrolled in this study and the levels of IgA, IgG, and IgM were determined before treatment and after 10 months of anticonvulsant therapy. Paired t-test was used to evaluate the data. p values<0.05 were considered significant. Results : The mean serum concentratrions of IgG was elevated in patients receiving anticonvulsants(p<0.05) but mean concentrations of IgA and IgM were not different significantly. Conclusion : Our results demonstrate that anticonvulsants elevate the serum concentrations of IgG level, suggesting that anticonvulsants may increase humoral immunity and decrease the opportunity of infectious disease, thus decreasing the convulsion.

Combined Method of Neuronal Cell-Inducible Vector and Valproic Acid for Enhanced Gene Expression under Hypoxic Conditions

윤여민,백다예,Dongsu Lee,Eunji Cheong,김장환,오진수,Yoonha Oh 한국조직공학과 재생의학회 2020 조직공학과 재생의학 Vol.17 No.1

BACKGROUND: Gene therapy shows the ability to restore neuronal dysfunction via therapeutic gene expression. The efficiency of gene expression and delivery to hypoxic injury sites is important for successful gene therapy. Therefore, we established a gene/stem cell therapy system using neuron-specific enolase promoter and induced neural stem cells in combination with valproic acid to increase therapeutic gene expression in hypoxic spinal cord injury. METHODS: To examine the effect of combined method on enhancing gene expression, we compared neuronal cellinducible luciferase levels under normoxia or hypoxia conditions in induced neural stem cells with valproic acid. Therapeutic gene, vascular endothelial growth factor, expression with combined method was investigated in hypoxic spinal cord injury model. We verified gene expression levels and the effect of different methods of valproic acid administration in vivo. RESULTS: The results showed that neuron-specific enolase promoter enhanced gene expression levels in induced neural stem cells compared to Simian Virus 40 promoter under hypoxic conditions. Valproic acid treatment showed higher gene expression of neuron-specific enolase promoter than without treatment. In addition, gene expression levels and cell viability were different depending on the various concentration of valproic acid. The gene expression levels were increased significantly when valproic acid was directly injected with induced neural stem cells in vivo. CONCLUSION: In this study, we demonstrated that the combination of neuron-specific enolase promoter and valproic acid induced gene overexpression in induced neural stem cells under hypoxic conditions and also in spinal cord injury depending on valproic acid administration in vivo. Combination of valproic acid and neuron-specific enolase promoter in induced neural stem cells could be an effective gene therapy system for hypoxic spinal cord injury.

흰쥐 두통 모델에 있어서 Sodium Valproate의 작용에 관한 연구

한진규,박민규,박건우,이대희 대한신경과학회 1998 대한신경과학회지 Vol.16 No.1

Epigenetically Upregulated T-Type Calcium Channels Contribute to Abnormal Proliferation of Embryonic Neural Progenitor Cells Exposed to Valproic Acid

( Ji-woon Kim ),( Hyun Ah Oh ),( Sung Rae Kim ),( Mee Jung Ko ),( Hana Seung ),( Sung Hoon Lee ),( Chan Young Shin ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.5

Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.

발프로익산이 인체 테논낭 섬유아세포의 생존에 미치는 영향

이시은(See Eun Lee),김재우(Jae Woo Kim) 대한안과학회 2018 대한안과학회지 Vol.59 No.11

목적: 발프로익산이 배양된 인체 테논낭 섬유아세포의 생존에 미치는 영향에 대해 알아보고자 하였다. 대상과 방법: 일차배양한 섬유아세포에 0, 0.25, 0.5, 1.0 mM 발프로익산과 0, 1.0, 2.5 μg/mL 미토마이신 C에 각각 또는 동시에 5일간 노출시킨 후 MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay를 이용하여 세포의 생존을 측정하였고, annexin-V/propidium iodide 이중염색 후 유세포 분석을 이용하여 세포고사의 정도를 측정하였다. 결과: 발프로익산은 농도에 비례하여 섬유아세포의 생존을 유의하게 저하시켰으며, 미토마이신 C를 추가한 경우 섬유아세포의 생존을 더욱 저하시켰다. 두 약제 모두 섬유아세포의 세포고사를 유발하였으나 발프로익산은 미토마이신 C에 비해 세포고사를 적게 유발하였다. 결론: 발프로익산은 섬유아세포의 생존을 저하시키며 세포고사를 유발한다. 또한 미토마이신 C를 병용한 경우 섬유아세포에 대한항증식효과가 더 나타날 것으로 생각된다. Purpose: To investigate the effects of valproic acid on the survival of cultured human Tenon’s capsule fibroblasts (HTFBs). Methods: Primary cultured HTFBs were exposed to 0, 0.25, 0.5, and 1.0 mM valproic acid with or without 0, 1.0, 2.5 μg/mL mitomycin C, and incubated for 5 days. Cell survival was assessed using an MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay and the degree of apoptosis was assessed by flow cytometry using annexin-V/propidium iodide double staining. Results: Valproic acid decreased the survival of HTFBs in a dose-dependent manner, and survival was further decreased by adding mitomycin C to valproic acid. Both valproic acid and mitomycin C induced apoptosis of HTFBs. Valproic acid induced less apoptosis than mitomycin C. Conclusions: Valproic acid decreased the cellular survival of HTFBs and induced apoptosis. The antiproliferative effects of valproic acid were further enhanced by the addition of mitomycin C.

CHK2 is involved in the p53-independent radiosensitizing effects of valproic acid

Choo, Dong Wan,Goh, Sung Ho,Cho, Young Woo,Baek, Hye Jung,Park, Eun Jung,Motoyama, Noboru,Kim, Tae Hyun,Kim, Joo Young,Kim, Sang Soo D.A. Spandidos 2017 Oncology letters Vol.13 No.4

<P>Radiotherapy is an effective treatment for the majority of types of localized solid cancer. However, the risk of side effects to the surrounding normal tissues limits radiotherapeutic approaches. Whilst the mechanism of action of valproic acid, an inhibitor of histone deacetylase, remains unknown, the inhibitor is a potential antineoplastic radiosensitizer. The present study demonstrated the <I>in vitro</I> radiosensitizing effects of valproic acid on the human breast cancer MCF7 cell line, and revealed that valproic acid increased the level of DNA breakage, apoptosis and senescence. In addition, western blot analyses revealed that valproic acid induced tumor suppressor protein (p)53 and p21 expression, and activated checkpoint kinase 2 (CHK2) in MCF7 cells and primary mouse embryonic fibroblasts. Notably, treatment with valproic acid also induced increases in the level of p21 protein levels and CHK2 activity in p53-null colon cancer HCT116 cells. Furthermore, the present study demonstrated that valproic acid-induced radiosensitization was largely dependent on the activity of CHK2. The results of the present study reveal that valproic acid may exhibit clinical utility with respect to increasing the anticancer efficacy of radiotherapy by affecting the level of p53.</P>