肽修饰的甲氨蝶呤体外抗肿瘤作用初步研究

本文以人乳腺癌MCF-7细胞及人红白血病K562细胞作为受试细胞,分别采用MTT比色法、流式细胞仪、RT-PCR技术检测促黄体激素释放激素肽修饰的甲氨蝶呤(methotrexate modified by luteinizing hormone-releasing hormone peptide,LH-RH-MTX)对细胞增殖的抑制作用以及对细胞周期和凋亡、LHRHR mRNA表达量的影响。结果显示,LH-RH-MTX对MCF-7细胞增殖的抑制作用明显高于K562细胞;相同浓度的LH-RH-MTX对MCF-7细胞增殖的抑制作用明显高于游离MTX,对鼠骨髓单核细胞的抑制作用明显小于游离MTX;经LH-RH-MTX作用后,S期细胞明显增加,细胞凋亡率明显升高,LHRHR mRNA的相对表达量明显下降。LH-RH可作为导向分子将药物靶向递送到LHRHR高表达的肿瘤细胞,降低药物的毒副作用,提高治疗指数。     

茶多酚与抗肿瘤药物联合作用对人鼻咽癌耐药细胞株HNE-1增殖抑制的影响

目的:检测茶多酚与4种抗肿瘤药物长春新碱、平阳霉素、5-氟尿嘧啶(5-Fu)、顺铂联合应用对放射线照射后的鼻咽癌耐药细胞株HNE-1(200)的增殖抑制作用。方法:采用MTT法筛选茶多酚及4种药物的低毒剂量,再测定低毒剂量的茶多酚与4种药物联合应用后对HNE-1(200)细胞的增殖抑制率。结果:茶多酚的低毒剂量为0.50mg.mL-1,该剂量下茶多酚与长春新碱、平阳霉素、5-Fu、顺铂联合应用后,对HNE-1(200)细胞的增殖抑制率均不同程度的增加,其增幅为单用抗肿瘤药的100%～300%。结论:茶多酚与4种抗肿瘤药物低剂量联合应用对人鼻咽癌耐药细胞具有明显的增殖抑制作用,提示茶多酚对该细胞株具有一定的耐药逆转作用。     

氧化苦参碱与抗肿瘤药物联合作用对HNE-1、HNE-1(200)细胞增殖抑制的影响

目的了解天然有效成分氧化苦参碱联合常用抗肿瘤药物(长春新碱、平阳霉素、5-Fu、顺铂)对HNE-1、HNE-1 (200)细胞的增殖抑制作用。方法本研究以鼻咽癌HNE-1细胞株以及由放射线照射诱导的耐药细胞株HNE-1(200)为研究对象,采用氧化苦参碱与低毒剂量的常用抗肿瘤药物联合应用,用MTT法测定其对实验细胞的增殖抑制率。结果对试验细胞抑制率低于20%的低毒浓度的长春新碱、平阳霉素、5-Fu、顺铂加入低毒浓度(0.5mg/mL)的氧化苦参碱后,使4种药物对细胞的抑制率增加,浓度越低,增幅越大。结论低浓度的天然药物与抗肿瘤药物联合应用对肿瘤细胞有明显的增殖抑制作用,并且时放射线照射诱导的耐药细胞株有一定的逆转作用。     

LHRHa与八聚精氨酸共修饰载氟尿嘧啶靶向脂质体的构建及其抗前列腺癌作用

目的 构建促黄体激素释放激素类似物(LHRHa)与八聚精氨酸(R8)共修饰载氟尿嘧啶(5-FU)脂质体(LHRHa/R8-LP-5-FU),对其前列腺癌靶向性以及治疗效果进行初步研究.方法 采用薄膜分散法制备LHRHa/R8-LP-5-FU,考察其形态、粒径、电位,并通过PC-3前列腺癌细胞定性和定量摄取实验考察其前列腺癌细胞靶向性.采用噻唑蓝(MTT)实验以及肿瘤球实验考察LHRHa/R8-LP-5-FU对PC-3细胞增殖抑制率.结果 所制备LHRHa/R8-LP-5-FU粒径为(115.0±15.2) nm,电位为(11.00±2.15) mV,5-FU的包封率(84.5±5.1)％.体外细胞摄取实验表明,PC-3细胞对LHRHa/R8-LP摄取效率分别是R8修饰脂质体(R8-LP)和LHRHa修饰脂质体(LHRHa-LP) 2.8和3.2倍(P＜0.01).细胞毒性实验结果显示,以0.9％氯化钠溶液为对照,LP-5-FU、R8-LP-5-FU、LHRHa-LP-5-FU和LHRHa/R8-LP-5-FU对PC-3细胞的增殖抑制率分别为(26.4±4.5)％,(39.5±4.2)％,(48.6±3.5)％和(82.5±4.3)％(P＜0.01).LHRHa/R8-LP-5-FU对肿瘤球的生长抑制作用明显高于其他脂质体.细胞毒性实验结果与细胞摄取实验结果一致.结论 LHRHa与细胞穿膜肽共修饰载5-FU脂质体具有良好的前列腺肿瘤细胞靶向性和抗肿瘤作用,是一种潜在的治疗前列腺癌的高效给药系统.     

5-氟尿嘧啶核苷前药脂质体对人鼻咽癌HNE-1细胞株增殖抑制与凋亡作用的影响

目的：研究5-氟尿嘧啶核苷前药脂质体对人鼻咽癌细胞株HNE-1细胞株增殖与凋亡作用的影响。方法本研究以人鼻咽癌HNE-1细胞株为研究对象,以5-氟尿嘧啶为对照,用四甲基偶氮唑蓝（MTT）法测定5-氟尿嘧啶核苷前药脂质体对HNE-1细胞的增殖抑制率;用流式细胞仪（FCM）测定5-氟尿嘧啶核苷前药脂质体作用与HNE-1细胞72h后细胞的凋亡率。结果5-氟尿嘧啶核苷前药脂质体对HNE-1细胞的IC50是5-氟尿嘧啶的1/3;浓度为0.043μg/mL 5-氟尿嘧啶和5-氟尿嘧啶核苷前药脂质体作用于HNE-1细胞的凋亡指数分别为（6.31±0.17）％、（19.53±1.79）％。结论本实验研究显示,与5-氟尿嘧啶相比较,5-氟尿嘧啶核苷前药脂质体对人鼻咽癌HNE-1细胞具有很好的生长增殖抑制作用,并且能够显著提高HNE-1细胞的凋亡率。     

青蒿琥酯对前列腺癌PC-3细胞的抑制作用

目的:观察青蒿琥酯对前列腺癌细胞株PC-3的体外作用,并探讨其可能作用机制。方法:应用光镜形态学、MTT法、流式细胞仪观察不同浓度青蒿琥酯在体外对前列腺癌细胞系PC-3的作用和对细胞DNA含量的影响。结果:青蒿琥酯对前列腺癌细胞系PC-3有明显的生长抑制作用,并能诱导细胞凋亡和抑制细胞增殖周期。结论:青蒿琥酯对前列腺癌PC-3细胞有明显生长抑制和凋亡诱导作用,提示青蒿琥酯有用于治疗激素非依赖性前列腺癌的可能性。     

甲氨蝶呤及重组人肿瘤坏死因子对体外培养软骨肉瘤细胞株的作用

目的:研究甲氨蝶呤(MTX)及重组人肿瘤坏死因子(rhTNF)对体外培养软骨肉瘤细胞株的作用。方法:采用细胞培养技术,将不同含量的MTX、rhTNF加入到培养的软骨肉瘤细胞株中,培养4d后,通过光学显微镜观察软骨肉瘤细胞株的形态学变化,MTT法观察软骨肉瘤细胞株的生长情况,以及采用荧光染色、流式细胞仪法观察软骨肉瘤细胞株的凋亡情况。结果:MTX和rhTNF使软骨肉瘤细胞的增殖受到明显抑制,凋亡细胞数显著增加(P<0.01),其作用随着药物浓度的增加而增强。联合应用MTX、rhTNF后细胞增殖抑制作用得到增强,凋亡细胞数亦增加。结论:MTX、rhTNF有一定的抗软骨肉瘤细胞活性,MTX、rhTNF间具有协同作用。     

穿琥宁对大肠癌HCT-8/5-FU耐药细胞株逆转作用的研究

目的:探讨中药制剂穿琥宁对HCT-8/5-FU多药耐药细胞株的影响.方法:观察0.4,1.2和2.4mg·mL-1穿琥宁作用下的HCT-8/5-FU多药耐药细胞株生长曲线,MTT法检测上述浓度下的细胞抑制率.MTT法、流式细胞仪PI染色法检测穿琥宁与化疗药物5-氟尿嘧啶(5-FU)、顺铂(DDP)和阿霉素(ADM)联合作用下,对HCT-8/5-FU耐药细胞的毒性作用和凋亡率.流式细胞仪罗丹明染色法和PI染色法探讨穿琥宁的作用机制.结果:0.4mg·mL-1穿琥宁生长曲线与正常对照组无明显差别,1.2mg·mL-1穿琥宁对细胞生长有轻度抑制作用,2.4mg·mL-1浓度有一定抑制,但细胞仍可生长.MTT法检测0.4,1.2,2.4mg·mL-1穿琥宁作用下,HCT-8/5-FU耐药细胞株的抑制率分别为7.2%,13.2%,21%.1.2mg·mL-1穿琥宁与5-FU,DDP,AMD联合作用,与这3种化疗药物单独作用比较细胞凋亡率分别为54.2%/26.4%;42.6%/13.6%;30.8%/14.2%,差异显著(P<0.01).罗丹明染色法提示穿琥宁的作用机制可能与影响P-170的活性有关.但穿琥宁本身并不诱导凋亡,对细胞周期也无影响.结论:低浓度穿琥宁对HCT-8/5-FU细胞无明显抑制作用;与5-FU,ADM,DDP联合作用,可增加上述化疗药物的毒性作用,使肿瘤细胞的凋亡率增高,其机制可能与抑制P-170功能有关.     

氧化苦参碱对鼻咽癌耐药细胞株HNE-1(200)耐药逆转机制的研究

目的:研究天然有效成分氧化苦参碱对鼻咽癌耐药细胞株HNE-1(200)耐药逆转的机制。方法:以放射线照射诱导的鼻咽癌耐药细胞株HNE-1(200)为研究对象,采用免疫细胞化学法、免疫印迹(Western Blot)法检测细胞P-糖蛋白(P-gp)表达的变化,用逆转录-聚合酶链反应(RT-PCR)检测多药耐药1基因(mdr1)的mRNA的改变。结果:氧化苦参碱作用于HNE-1(200)细胞24h后,免疫细胞化学方法和Western Blot显示:人鼻咽癌(P-gp)表达下调;RT-PCR显示:HNE-1、HNE-1(200)细胞的mdr1表达无差异。结论:氧化苦参碱能通过下调P-gp表达,在一定程度上逆转耐药,但是mRNA表达并无变化,说明鼻咽癌多药耐药引起P-gp表达上调受多种机制控制。     

葡萄汁对人前列腺癌PC-3细胞的凋亡作用

目的研究葡萄汁对人前列腺癌PC-3细胞的影响。方法将低、中、高剂量(分别为16、32和64μl/ml)的葡萄汁加入体外培养的人前列腺癌PC-3细胞,检测葡萄汁对PC-3细胞的毒性作用,用单细胞凝胶电泳测其对DNA损伤作用,流式细胞术测细胞凋亡,免疫组化法测凋亡相关基因Bax、Bcl-2的表达。结果3种剂量的葡萄汁能抑制人前列腺癌PC-3细胞增殖;DNA迁移长度与彗星细胞拖尾率逐渐增高,拖尾细胞率最高为71%;能诱导人前列腺癌PC-3细胞凋亡,细胞凋亡率分别是14.5%3、2.1%和40.5%,促凋亡基因Bax表达率分别是36.8%、50.4%和64.8%;抑凋亡基因Bcl-2表达率依次为39.1%、25.0%和12.4%。结论葡萄汁可抑制人前列腺癌PC-3细胞增长,诱导其细胞凋亡,能上调促凋亡基因Bax的表达,下调抑凋亡基因Bcl-2的表达。     

亚甲蓝对结肠癌细胞系Lovo的杀伤和抑制作用

为探讨亚甲蓝对体外培养的人大肠癌细胞的抗肿瘤作用 ,采用直接杀伤实验、细胞生长抑制实验和细胞集落形成能力实验方法研究了亚甲蓝对体外培养的人大肠癌细胞系Lovo的作用 ,同时用透射电镜技术观察了该药对癌细胞的损伤部位 .结果显示 13 2 5 μmol/L亚甲蓝作用2 4h可杀死 79 4%的大肠癌细胞 ,5 3μmol/L亚甲蓝作用 2 4h可杀死全部大肠癌细胞 ,0 2 7μmol/L亚甲蓝即可明显抑制人结肠癌细胞的增殖 .透射电镜观察显示亚甲蓝损伤细胞的部位在线粒体 .研究结果表明 ,亚甲蓝对体外培养的人大肠癌细胞Lovo具有显著的杀伤和抑制作用 ,其损伤癌细胞的部位在线粒体     

Human epithelial carcinoma cytotoxicity and inhibition of DMBA/TPA induced squamous cell carcinoma in Balb/c mice by Acacia catechu heartwood

Objectives Acacia catechu heartwood contains significant amounts of polyphenolic compounds that exhibit powerful antioxidant activity. The purpose of this study was to evaluate the cytotoxicity of A. catechu heartwood extracts in a human epithelial carcinoma cell line (A431) and antitumour activity against DMBA/TPA induced squamous cell carcinoma in Balb/c mice. Methods Various extracts, including aqueous, ethyl acetate, chloroform and n‐hexane, were tested for cytotoxic properties on a human epithelial carcinoma cell line (A431) by using MTT, sulforhodamine B and lactate dehydrogenase leakage assays. The standardized A. catechu heartwood aqueous extract (AQCE) was further evaluated for antitumour activity against 7,12‐dimethylbenz[a]anthracene (DMBA)/12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) induced skin carcinoma in Balb/c mice. Key findings The results showed that administration of AQCE showed a dose‐dependent growth inhibition response, with an IC50 value of 78.56 µg/ml. Tumour incidence was significantly decreased (P < 0.001) to 30% with AQCE compared with 100% in the DMBA/TPA group. The AQCE was also found to significantly upregulate different antioxidant enzymes in skin and liver tissue. Conclusions The results suggest that AQCE may exert its chemopreventive activity by acting as an antioxidant.     

Effect of luteinizing hormone-releasing hormone analogs containing cytotoxic radicals on growth of estrogen-independent MXT mouse mammary carcinoma in vivo.

Cytotoxic luteinizing hormone-releasing hormone (LH-RH) analogs, AJ-004 (agonist [D-Lys6]LH-RH linked to methotrexate (MTX)), T-98 ([D-Lys6]LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone) (G-HMAQ) and T-121/B (antagonist containing two residues of G-HMAQ) were tested in female BDF1 mice bearing MXT ((3.2)/Ovex) estrogen-independent mammary tumors. All three cytotoxic LH-RH analogs, administered from Alzet Osmotic Minipumps for 3 weeks, produced a significant inhibition of tumor growth. The effects of T-98 and T-121/B were superior to those obtained by treatment with equimolar doses of cytotoxic moiety anthraquinone or the LH-RH carrier alone. We assume that cytotoxic LH-RH analogs have a combined hormonal and cytotoxic activity with a reduced toxicity after administration in vivo. This is the first demonstration of in vivo tumor inhibition by targeted LH-RH analogs bearing cytotoxic radicals.     

Liposome encapsulation enhancement of methotrexate sensitivity in a transport resistant human leukemic cell line

A stable mutant of human leukemia CCRF/CEM cells has recently been isolated which is transport resistant for methotrexate (MTX). Encapsulation of MTX in cationic unilamellar liposomes increased the association of the drug 5-fold with the sensitive, and 50-fold with the resistant, cells as compared to the uptake of free drug. The liposome-mediated associations of MTX with sensitive and transport deficient cell lines were similar. Cytostatic studies demonstrated that liposome encapsulation increased MTX activity 4-fold towards the transport resistant cell line. The addition of cholesterol to the vesicles decreased their effectiveness. A 4-fold increase in drug sensitivity due to encapsulation may allow such transport resistant tumor cells to become responsive to chemotherapeutic doses of MTX which are currently feasible in human clinical protocols.     

Use of analogs of peptide hormones conjugated to cytotoxic radicals for chemotherapy targeted to receptors on tumors

Specific receptors for luteinizing hormone-releasing hormone (LH-RH), somatostatin, bombesin, and other peptides are found on various cancers. We review the development of cytotoxic analogs of LH-RH, somatostatin, and bombesin/gastrin releasing peptide (GRP) designed for targeting chemotherapy to peptide receptors on various cancers. Cytotoxic analogs of LH-RH, AN-152 and AN-207, containing doxorubicin (DOX) or 2-pyrrolino-DOX (AN-201), respectively, target LH-RH receptors and may be used for the treatment of prostatic and urinary bladder (urothelial), breast, ovarian and endometrial cancers, non-Hodgkin's lymphomas, melanomas, and renal cell carcinomas. DOX and AN-201 have also been incorporated into the cytotoxic analogs of somatostatin, AN-162 and AN-238, respectively, which are targeted to receptors for somatostatin in prostatic, mammary, ovarian, gastric, renal, colorectal and pancreatic cancers, non-Hodgkin's lymphomas, as well as glioblastomas and lung cancers. They are found to suppress the growth of these tumors and their metastases. A cytotoxic analog of bombesin/GRP, AN-215, containing 2-pyrrolino-Dox, has also been synthesized and shown to inhibit growth of various human cancer lines expressing receptors for bombesin/GRP. The toxicity, pharmacokinetics and maximum tolerated doses of AN-152 were assessed in a phase I clinical trial in women with ovarian or endometrial cancer. Disease stabilization and objective responses were found. Analog AN-152 is now in phase II clinical trials. Phase I/II studies with AN-152 in men with hormone-independent relapsed prostate cancer and patients with pancreatic and bladder cancers are pending. Targeted cytotoxic peptide analogs could provide a more efficacious and less toxic therapy for various cancers.     

Methotrexate conjugated to gold nanoparticles inhibits tumor growth in a syngeneic lung tumor model

Methotrexate (MTX), a stoichiometric inhibitor of dihydrofolate reductase, is a chemotherapeutic agent for treating a variety of neoplasms. Impairment of drug import into cells and increase in drug export from cells may render cells resistant to MTX. MTX, when locally administered in a soluble form, is rapidly absorbed through capillaries into the circulatory system, which may also account for therapeutic failure in patients. To retain MTX within tumor cells for longer duration and alter its pharmacokinetic behavior, we proposed a new formulation of MTX bound to the gold nanoparticle (AuNP) that serves as drug carriers. In this study, we developed the MTX-AuNP conjugate and examined its cytotoxic effect in vitro and antitumor effect in vivo. Spectroscopic examinations revealed that MTX can be directly bound onto AuNP via the carboxyl group (-COOH) to form the MTX-AuNP complex and kinetically released from the nanoparticles. The accumulation of MTX is faster and higher in tumor cells treated with MTX-AuNP than that treated with free MTX. Notably, MTX-AuNP shows higher cytotoxic effects on several tumor cell lines compared with an equal dose of free MTX. This can be attributed to the "concentrated effect" of MTX-AuNP. Administration of MTX-AuNP suppresses tumor growth in a mouse ascites model of Lewis lung carcinoma (LL2), whereas an equal dose of free MTX had no antitumor effect. In conclusion, these results suggest that by combining nanomaterials with anticancer drugs MTX-AuNP may be more effective than free MTX for cancer treatment.     

Determining the cytotoxicity of methotrexate‐loaded microemulsion on human breast,ovarian, and prostate carcinoma cell lines: a new modality for an old drug

The main objective of this study was to develop an optimal methotrexate (MTX) microemulsion (M‐MTX) and to evaluate the suppressive effect of MTX‐loaded microemulsion on human breast, ovarian, and prostate carcinoma cell lines. The microemulsion was made up of corn‐oil as the oil phase, a mixture of Cremophore EL and Span 80 as surfactants, and isopropyl alcohol as co‐surfactant and 0.1 N NaOH as the aqueous phase. MTX (0.1 mg/mL MTX ) was added into the microemulsion at the last stage. The pH of M‐MTX was adjusted to pH 8±0.1 and the physicochemical stability of the formulation was observed. The particle size distribution was measured by Zetasizer 3000 HSA. The mean droplet diameters of M‐MTX were determined as 13.3±0.1 nm (poly dispersity index=530±0.01). The antitumor effects of M‐MTX were examined on human breast (MCF‐7), ovarian (OVCAR), and prostate (DU 145) carcinoma cell lines. It was clearly demonstrated that M‐MTX had a significant cytotoxic effect on different carcinoma cell lines and the cytotoxic effect of M‐MTX was significantly more than that of commercial preparation (C‐MTX) (P<0.05). According to the in vitro cytotoxicity studies, it can be concluded that when MTX was incorporated into the microemulsion (M‐MTX), which is a new drug carrier system, it suppresses tumour cell growth on multiple tumor lines. These results indicate that M‐MTX may be effective as an antitumor agent that induces apoptosis. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

Methotrexate and 5-aminoimidazole-4-carboxamide riboside exert synergistic anticancer action against human breast cancer and hepatocellular carcinoma

Aim:

To investigate the influences of methotrexate (MTX) on the anticancer actions and pharmacokinetics of 5-aminoimidazole-4-carboxamide riboside (AICA riboside) in human breast cancer and hepatocellular carcinoma.

Methods:

Human breast cancer cell line MCF-7 and human hepatocellular carcinoma cell line HepG2 were examined. The cell proliferation was assessed using a sulforhodamine B assay. Western blotting and radioactivity assays were used to analyze the phosphorylation of AMPK. The DNA synthesis was analyzed with BrdU incorporation. Nude mice bearing MCF-7 cell xenografts were used to for in vivo study. MTX (50 mg/kg, ip, per week) and AICA riboside (200 mg/kg, ip, every other day) were administered the animals for 2 weeks. The concentrations of AICA riboside and its active metabolite AICA ribotide in the plasma and tumors were measured with HPLC.

Results:

Synergistic cytotoxicity in vitro was observed with MTX (0.1, 0.5, and 1 μmol/L) combined with AICA riboside (0.25–1 mmol/L) in MCF-7 cells, and with MTX (0.5 and 1 μmol/L) combined with AICA riboside (0.5 and 1 mmol/L) in HepG2 cells. MTX (1 μmol/L) significantly enhanced the AICA riboside-induced AMPK activation and BrdU incorporation in both MCF-7 and HepG2 cells. Co-treatment with MTX and AICA riboside exerted more potent inhibition on the tumor growth in nude mice than either drug alone. After injection of AICA riboside (200 mg/kg, iv) in nude mice bearing MCF-7 xenografts, MTX (50 mg/kg, iv) significantly increased the concentrations of AICA riboside and its active metabolite AICA ribotide in tumors.

Conclusion:

MTX and AICA riboside exert synergistic anticancer action against MCF-7 and HepG2 cells in vitro and in vivo. MTX increases the concentration of AICA riboside and its active metabolite AICA ribotide in tumors in vivo.     

Controlled release of methotrexate from w/o microemulsion and its in vitro antitumor activity

The objective of this study was to prepare the microemulsion of methotrexate (M-MTX) for oral use and to investigate the suppressive effect of MTX-loaded microemulsion on MCF-7 human breast cancer cells. At the same time this effect of M-MTX was compared with those of a solution of the drug (Sol-MTX). Microemulsion was composed of soybean oil as oil phase, a mixture of Cremophore EL and Span 80 as surfactants, and isopropyl alcohol as co-surfactant, and 0.2 N NaOH as the aqueous phase. MTX was added into microemulsion at the last stage. We clearly demonstrated that M-MTX had a significant cytotoxic effect on breast cancer cell lines and the cytotoxic effect of M-MTX was significantly more than that of solutions (p < 0.05) and IC(50) value for M-MTX was 40 ng/mL. We also examined M-MTX and Sol-MTX on a model biological environmental model. For this purpose a gastrointestinal cell culture model, the Caco-2 cell line, was used to investigate the cytotoxic effects of the polymeric carrier and its effect on the cell monolayer integrity. The differences between the viability of cells for M-MTX and Sol-MTX were significantly different when applied to ANOVA according to 2 x 8 factorial randomized design (p:0.016; for alpha: 0.05, power : 0.695). According to the in vitro cytotoxicity studies, we concluded that when MTX was incorporated into the microemulsion (M-MTX), which is a new drug carrier system, it suppresses tumour cell growth on multiple tumor lines. These results indicate that M-MTX may exert a low cytotoxic effect on normal cells and may be effective as an antitumor agent that induces apoptosis.