Herbal Science Research - cancer

[...] Ratanhia-based herbal oral care products for the prophylaxis of oral mucositis in cancer chemotherapy patients: a clinical

Site Editor — Fri, 02 Nov 2007 15:47:21 -0700

Administration of Ratanhia-based herbal oral care products for the prophylaxis of oral mucositis in cancer chemotherapy patients: a clinical trial.: Evid Based Complement Alternat Med. 2007 Sep; 4(3): 361-6 Tiemann P, Toelg M, Ramos F MH

Oral complications are a common side effect of cancer chemotherapy, as antineoplastic agents affect both the immune system and the oral mucosa. This study demonstrates preventive and therapeutic effects of dental treatment and regular use of Weleda Ratanhia-Mundwasser((R)) (herbal mouthwash) and Weleda Pflanzen-Zahngel((R)) (herbal toothgel) on oral mucositis during chemotherapy. Thirty-two female patients with breast cancer starting on chemotherapy were evaluated in this study. Plaque index, gingival index, degree of mucositis and 10 single symptoms were monitored once weekly for four consecutive weeks. After four weeks, plaque and gingival indexes were slightly decreased compared to baseline values. The degree of mucositis was increased by one grade in 15.6 % of the patients and over 70 % remained without symptoms. On the whole, single symptoms decreased from day 7 since beginning of chemotherapy to day 28. Mucositis symptoms were moderate in severity, and the results indicate a positive influence of using Weleda Ratanhia-Mundwasser and Weleda Pflanzen-Zahngel. Further studies might be promising.

Biotransformation of Green Tea Polyphenols and the Biological Activities of Those Metabolites.

Site Editor — Fri, 02 Nov 2007 06:23:16 -0700

Biotransformation of Green Tea Polyphenols and the Biological Activities of Those Metabolites.: Mol Pharm. 2007 Oct 27; Authors: Lambert JD, Sang S, Yang CS

Green tea ( Camellia sinensis, Theaceae) and its major polyphenol constituents, the catechins, have been reported to have many health benefits including the prevention of cancer and heart disease. Many mechanisms of action have been proposed based on in vitro models; however, the importance of most of these mechanisms remains to be determined in vivo. The bioavailability and biotransformation of tea catechins play a key role in determining the importance of various mechanisms in vivo. Likewise, the biological activity and bioavailability of tea catechin metabolites, an understudied area, are important in understanding the potential beneficial effects of tea. In this article, we review the data available on the biotransformation of the tea catechins and the limited data set available on the biological activities of the catechin metabolites. Careful interpretation of available data, carefully designed animal experiments, and integration of bioavailability and biological activity data are needed if the disease preventive activity of tea is to be understood. We hope this article will spark research efforts on some of the important questions regarding tea polyphenol bioavailability, biotransformation, and the biological activities of tea catechin metabolites.

PMID: 17963356 [PubMed - as supplied by publisher]

Black cohosh (Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients.

Site Editor — Fri, 02 Nov 2007 05:52:36 -0700

Black cohosh (Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients.: Support Care Cancer. 2007 Aug;15(8):913-21 Authors: Walji R, Boon H, Guns E, Oneschuk D, Younus J

GOALS OF WORK: Black cohosh is commonly used to treat hot flashes and other symptoms associated with menopause. It is thought to have multiple mechanisms of action, including potential phytoestrogenic properties. This has caused some concern about its use by patients with hormone-sensitive cancer. This paper will present the results of a systematic review of the safety and efficacy of black cohosh (Cimicifuga racemosa [L.] Nutt.) in patients with cancer. MATERIALS AND METHODS: A critical assessment of clinical (n = 5) and preclinical (n = 21) studies of black cohosh and cancer (breast and prostate) to treat hot flashes and other related symptoms is presented. In addition, clinical studies, case reports, animal studies, and in vitro assessments of the safety of black cohosh for patients with hormonally sensitive cancers is summarized and interpreted. MAIN RESULTS: In general, the research assessing efficacy of black cohosh for the treatment of hot flashes in women with breast cancer is inconclusive. There is laboratory evidence of antiproliferative properties but no confirmation from clinical studies for a protective role in cancer prevention. Black cohosh seems to have a relatively good safety profile. Concerns about liver toxicity are inconclusive. With relevance to cancer patients, black cohosh also seems not to exhibit phytoestrogenic activity and is in fact possibly an inhibitor of tumor growth. CONCLUSIONS: The use of black cohosh appears to be safe in breast cancer patients without risk for liver disease, although further research is needed in this and other populations.

PMID: 17602247 [PubMed - indexed for MEDLINE]

Suppressive effect of a standardized mistletoe extract on the expression of activatory NK receptors and function [...]

Site Editor — Fri, 02 Nov 2007 05:51:27 -0700

Suppressive effect of a standardized mistletoe extract on the expression of activatory NK receptors and function of human NK cells.: J Clin Immunol. 2007 Sep;27(5):477-85 Authors: Lee SJ, Son YO, Kim H, Kim JY, Park SW, Bae JH, Kim HH, Lee EY, Chung BS, Kim SH, Kang CD

Despite long-term use of mistletoe extracts for cancer treatment, their mode of action remains elusive. In this study, it was studied in vitro if mistletoe extract is able to modulate the expression of natural cytotoxic receptors (NCRs) and NKG2D receptor, which stimulate natural killer cell-mediated cytotoxicity. Unexpectedly, a mistletoe extract, ABNOBA viscum Fraxini, inhibited the expression level of NKp46 and NKG2D receptors in dose- and time-dependent manners. The levels of NKp30 and NKG2D receptors were remarkably induced and NKp44 was slightly induced after 48 h treatment with IL-2 and IL-15 in both mRNA and surface expression. The activatory NK receptors were not induced significantly after treatment with IL-12, IL-18, and IL-21 for 48 h. Induction of activatory NK receptors by IL-2 and IL-15 was suppressed almost to the untreated levels by treatment with mistletoe extract, which appeared to induce apoptosis of NK cells in a dose-dependent manner. However, the treatment with IL-2 and IL-15 did not prevent the mistletoe-induced NK-cell death. Mistletoe extract inhibited significantly the cytotoxic activity of resting and IL-2- or IL-15-stimulated NK cells. These results suggest that inhibition of survival and function of NK cells by mistletoe extract may curtail in part the therapeutic effects of mistletoe.

PMID: 17530391 [PubMed - indexed for MEDLINE]

A novel polyacetylene significantly inhibits angiogenesis and promotes apoptosis in human endothelial cells [...]

Site Editor — Fri, 02 Nov 2007 05:43:20 -0700

A novel polyacetylene significantly inhibits angiogenesis and promotes apoptosis in human endothelial cells through activation of the CDK inhibitors and caspase-7.: Planta Med. 2007 Jun;73(7):655-61 Authors: Wu LW, Chiang YM, Chuang HC, Lo CP, Yang KY, Wang SY, Shyur LF

A novel bioactive polyacetylene compound, 1,2-dihydroxy-5(E)-tridecene-7,9,11-triyne (compound 1), was identified from the Bidens pilosa extract using an ex vivo primary human umbilical vein endothelium cell (HUVEC) bioassay-guided fractionation protocol. Our results demonstrate that compound 1 (at 2.5 microg/mL) possessed significant anti-angiogenic effects, as manifested by an inhibition of HUVEC proliferation, migration, and the formation of tube-like structures in collagen gel. Moreover, compound 1 induced HUVECs to undergo cell death in a concentration- and time-dependent manner. The mechanisms underlying these pharmacological effects include reduced expression of cell cycle mediators such as CDK4, cyclins D1 and A, retinoblastoma (Rb) and vascular endothelial growth factor receptor 1 (VEGFR-1), and promotion of caspase-mediated activation of CDK inhibitors p21(Cip1) and p27(Kip). Moreover, apoptotic induction in HUVECs mediated by compound 1 was found to be in part through overexpression of FasL protein, down-regulation of anti-apoptotic Bcl-2, and activation of caspase-7 and poly(ADP-ribose) polymerase. This study demonstrates the potent anti-angiogenic and apoptotic activities of compound 1, suggesting that phytocompounds such as polyacetylenes deserve more attention regarding their potential as candidates for anti-angiogenic therapeutics.

PMID: 17559025 [PubMed - indexed for MEDLINE]

Moving toward bioadjuvant approaches to head and neck cancer prevention.

Site Editor — Mon, 22 Oct 2007 18:27:34 -0700

Moving toward bioadjuvant approaches to head and neck cancer prevention.: Int J Radiat Oncol Biol Phys. 2007;69(2 Suppl):S132-5 Authors: Saba NF, Hammond A, Shin DM, Khuri FR

Head and neck squamous cell carcinoma affects >45,000 Americans annually. Patients who are successfully treated for their primary tumor are at high risk of developing a second primary tumor, making effective preventive strategies highly desirable for this disease. Although a landmark study in 1990 suggested some benefit of high-dose retinoids in head and neck cancer prevention, subsequent trials using more tolerable doses have shown limited clinical success. Newer preventive strategies have included bioadjuvant therapy combining retinoids with interferon and alpha-tocopherol, combinations of molecularly targeted agents, and oncolytic viruses. Furthermore, considerable evidence has supported a cancer protective role for several nutrients, including green tea and curcumin analogs. Natural compounds such as these with favorable long-term safety profiles might be particularly suited to the cancer prevention setting, in which patients will usually tolerate only moderate risk and toxicity.

PMID: 17848282 [PubMed - in process]

The plant alkaloid sanguinarine is a potential inhibitor of follicular angiogenesis.

Site Editor — Mon, 22 Oct 2007 18:18:06 -0700

The plant alkaloid sanguinarine is a potential inhibitor of follicular angiogenesis.: J Reprod Dev. 2007 Jun;53(3):573-9 Authors: Basini G, Santini SE, Bussolati S, Grasselli F

Sanguinarine (SA), a phytobiotic from Sanguinaria Canadensis, has been demonstrated to inhibit vessel growth. Current restrictions on the use of antibiotic growth promoters have motivated addition of this alkaloid as a naturally appetizing feed additive for farm animals. However, concern may araise since angiogenesis is a fundamental event in ovarian follicle growth. Therefore, the aim of this study was to evaluate the potential negative role of SA in follicular angiogenesis. For this purpose, we studied the effect of 300 nM SA on the production of vascular endothelial growth factor (VEGF) by swine granulosa cells from follicles >5 mm and on the activation of Akt, the main effector of the VEGF signalling pathway. In addition, the potential interference of SA in vessel development was tested in an in vitro angiogenesis bioassay. SA inhibited both VEGF production and VEGF-induced Akt activation in swine granulosa cells. Moreover, it was able to block vessel growth induced by VEGF. Taken together, our results suggest that SA could be detrimental to follicular angiogenesis, and therefore supplementation of feed with this alkaloid should be carefully considered.

PMID: 17310078 [PubMed - indexed for MEDLINE]

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Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells [...]

Site Editor — Sun, 21 Oct 2007 05:54:24 -0700

Epigallocatechin-3-gallate inhibits the invasion of human oral cancer cells and decreases the productions of matrix metalloproteinases and urokinase-plasminogen activator.: J Oral Pathol Med. 2007 Nov;36(10):588-93 Authors: Ho YC, Yang SF, Peng CY, Chou MY, Chang YC

Background: Green tea polyphenols are considered beneficial to human health, especially as cancer chemopreventive agents in recent years. Epigallocatechin- 3-gallate (EGCG), the most abundant polyphenol in green tea, has been proven to suppress colonic tumorigenesis in animal and epidemiological studies, whereas its role in the oral carcinogenesis remains to be elucidated. Methods: Cytotoxicity, invasion, and migration assays were used to investigate the effects of human oral cancer cell line OC2 cells exposed to EGCG. To look at the precise involvement of EGCG in cancer metastasis, gelatin zymography and casein zymography were performed to evaluate the impacts of EGCG on matrix metalloproteinase (MMP)-2, MMP-9, and urokinase plasminogen activator (uPA) secretion in OC2 cells. Results: EGCG exhibited a dose-dependent inhibitory effect on the invasion and migration of OC2 cells in the absence of cytotoxicity (P < 0.05). EGCG was also found to decrease the expressions of MMP-2, MMP-9, and uPA in a concentration-dependent manner (P < 0.05). Conclusion: Taken together, these results suggest that EGCG could inhibit the invasion and migration of human oral cancer cells and that the effects may partially because of the decreased productions of MMP-2, MMP-9, and uPA.

PMID: 17944751 [PubMed - in process]

Reduction of PSA values by combination pharmacological therapy in patients with chronic prostatitis [...].

Site Editor — Wed, 26 Sep 2007 19:05:40 -0700

Reduction of PSA values by combination pharmacological therapy in patients with chronic prostatitis: implications for prostate cancer detection.: Arch Ital Urol Androl. 2007 Jun;79(2):84-92 Authors: Magri V, Trinchieri A, Montanari E, Del Nero A, Mangiarotti B, Zirpoli P, de Eguileor M, Marras E, Ceriani I, Vral A, Perletti G

We identified from our clinical database a total of 471 patients affected by cat. II chronic bacterial prostatitis (CBP), cat. III (IIIa and IIIb) chronic pelvic pain syndrome (CP/CPPS), or cat. IV asymptomatic inflammatory prostatitis (AIP), according to NIH criteria. 132 intent-to-treat patients, showing levels of PSA > or =4 ng/mL, were subjected to a 6-week course of combination pharmacological therapy with 500 mg/day ciprofloxacin, 500 mg/day azithromycin (3 days/week), 10 mg/day alfuzosin and 320 mg b.i.d. Serenoa repens extract. At the end of treatment, 111 per-protocol patients belonging to all categories of prostatitis showed a total 32.5% reduction of PSA levels. In the same group, 66 patients (59.4%) showed "normalization" of PSA values under the 4 ng/mL limit. Patients affected by cat. IIIb CP/CPPS showed the highest PSA reduction and normalization rates (40% and 68.4%, respectively). Follow-up data show that, after a marked, significant reduction at completion of therapy, PSA levels, urine peak flow rates and NIH-CPSI symptom scores remained constant or decreased throughout a period of 18 months in patients showing normalization of PSA values. Prostatic biopsy was proposed to 45 patients showing persistently high PSA values (> or = 4 ng/mL) at the end of treatment. Fourteen patients rejected biopsy; of the remaining 31, 10 were diagnosed with prostate cancer. Four months after a first biopsy, a second biopsy was proposed to the 21 patients with a negative first diagnosis and persistently elevated PSA levels. Three patients rejected the procedure; of the remaining 18, four were diagnosed with prostatic carcinoma. In summary, combination pharmacological therapy decreased the number of patients undergoing prostatic biopsy from 111 to 45. Normalization of PSA values in 59.4% of patients--not subjected to biopsy--increased the prostate cancer detection rate from 12.6% (14/111) to 31.1% (14/45). The reduction of PSA after a 6-week course of therapy was calculated in patients affected by cat. II, IIIa, IIIb and IV prostatitis after stratification with respect to the concomitant presence or absence of benign prostatic hyperplasia (BPH). PSA was reduced by 41% in cat. II CBP patients without BPH, compared to a 12.7% reduction in patients affected by BPH. Cat. IIIa CP/CPPS patients without BPH showed a 58.3% reduction of PSA levels, compared to a 20.7% reduction observed in CPPS/BPH patients. These data show that the presence of BPH may prevent the reduction of PSA induced by combination pharmacological therapy, and suggest that care has to be taken in the adoption of PSA as a marker of therapeutic efficacy in the presence of confounding factors like BPH. PSA should in our opinion be used as a significant component of a strategy integrating multiple diagnostic approaches.

PMID: 17695414 [PubMed - indexed for MEDLINE]

Human hair growth enhancement in vitro by green tea epigallocatechin-3-gallate (EGCG).

Site Editor — Wed, 26 Sep 2007 18:49:37 -0700

Human hair growth enhancement in vitro by green tea epigallocatechin-3-gallate (EGCG).: Phytomedicine. 2007 Aug;14(7-8):551-5 Authors: Kwon OS, Han JH, Yoo HG, Chung JH, Cho KH, Eun HC, Kim KH

Green tea is a popular worldwide beverage, and its potential beneficial effects such as anti-cancer and anti-oxidant properties are believed to be mediated by epigallocatechin-3-gallate (EGCG), a major constituent of polyphenols. Recently, it was reported that EGCG might be useful in the prevention or treatment of androgenetic alopecia by selectively inhibiting 5alpha-reductase activity. However, no report has been issued to date on the effect of EGCG on human hair growth. This study was undertaken to measure the effect of EGCG on hair growth in vitro and to investigate its effect on human dermal papilla cells (DPCs) in vivo and in vitro. EGCG promoted hair growth in hair follicles ex vivo culture and the proliferation of cultured DPCs. The growth stimulation of DPCs by EGCG in vitro may be mediated through the upregulations of phosphorylated Erk and Akt and by an increase in the ratio of Bcl-2/Bax ratio. Similar results were also obtained in in vivo dermal papillae of human scalps. Thus, we suggest that EGCG stimulates human hair growth through these dual proliferative and anti-apoptotic effects on DPCs.

PMID: 17092697 [PubMed - indexed for MEDLINE]

[...] effects of Cimicifuga racemosa [...] on the estrogen receptor positive human breast cancer cell line MCF-7.

Site Editor — Sat, 22 Sep 2007 18:18:28 -0700

Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7.: BMC Pharmacol. 2007 Sep 20; 7(1): 11 Gaube F, Wolfl S, Pusch L, Kroll TC, Hamburger M

ABSTRACT: BACKGROUND: Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, the molecular mode of action and the active principles are presently not clear. Previously published data have been largely contradictory. We, therefore, investigated the effects of a lipophilic Cimicifuga rhizome extract and cycloartane-type triterpenoids on the estrogen receptor positive human breast cancer cell line MCF-7. RESULTS: Both extract and purified compounds clearly inhibited cellular proliferation. Gene expression profiling with the extract allowed us to identify 431 regulated genes with high significance. The extract induced expression pattern differed from those of 17beta-estradiol or the estrogen receptor antagonist tamoxifen. We observed a significant enrichment of genes in an anti-proliferative and apoptosis-sensitizing manner, as well as an increase of mRNAs coding for gene products involved in several stress response pathways. These functional groups were highly overrepresented among all regulated genes. Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1. In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated. Real-Time RT-PCR analysis of 13 selected genes was conducted after treatment with purified compounds - the cycloartane-type triterpene glycoside actein and triterpene aglycons - showing similar expression levels compared to the extract. CONCLUSION: No estrogenic but antiproliferative and proapoptotic gene expression was shown for black cohosh in MCF-7 cells at the transcriptional level. The effects may be results of the activation of different pathways. The cycloartane glycosides and - for the first time - their aglycons could be identified as an active principle in black cohosh.

[Management of capecitabine-induced hand-foot syndrome by local phytotherapy]

Site Editor — Sat, 22 Sep 2007 18:03:19 -0700

[Management of capecitabine-induced hand-foot syndrome by local phytotherapy]: Wien Med Wochenschr. 2007; 157(13-14): 337-42 Kern E, Schmidinger M, Locker GJ, Kopp B

The so-called hand-foot syndrome (HFS) is a dose-limiting side effect with only rare therapeutic options in cancer patients treated with capecitabine (Xeloda). Depending on the intensity of the skin reaction dose reduction, interruption or even the break-off of capecitabine therapy is necessary. We therefore try to describe a new and promising alternative treatment of the hand-foot syndrome, a local therapy with a mixture of herbal medicinal products mainly consisting of hand- and foot baths, and present the promising results of this treatment modality observed in 11 consecutive patients.

Effect of Echinacea purpurea tincture and its polysaccharide complex on the efficacy of cytostatic therapy of transferred tumors

Site Editor — Sat, 22 Sep 2007 17:46:05 -0700

[Effect of Echinacea purpurea tincture and its polysaccharide complex on the efficacy of cytostatic therapy of transferred tumors]: Eksp Klin Farmakol. 2007 May-Jun; 70(3): 33-5 Razina TG, Lopatina KA, Zueva AM, Gur'ev AM, Krylova SG, Amosova EN

Experiments on C57LB/6 mice with transplanted Luis lung carcinoma showed that the officinal Echinacea purpurea preparation did not influence the efficacy of cytostatic therapy. This echinacea preparation did not change the development of metastases and even stimulated the tumor growth. In contrast, a hydrophilic polysaccharide complex isolated from echinacea increased the antitumor and antimetastatic activity of cyclophosphamide.

Schisandrol A from Schisandra chinensis reverses P-glycoprotein-mediated multidrug resistance by affecting Pgp-substrate complex

Site Editor — Fri, 13 Jul 2007 18:30:42 -0700

Schisandrol A from Schisandra chinensis reverses P-glycoprotein-mediated multidrug resistance by affecting Pgp-substrate complexes.: Planta Med. 2007 Mar;73(3):212-20 Authors: Fong WF, Wan CK, Zhu GY, Chattopadhyay A, Dey S, Zhao Z, Shen XL

Recent studies have shown that dibenzocyclooctadiene lignans may reverse P-glycoprotein-mediated multidrug resistance (Pgp-MDR) in cancer cells; however, the mechanism of action remains unknown. Through screening of herbs, we found that schisandrol A (SCH) isolated from Fructus Schisandrae (the dried fruit of Schisandra chinensis (Turcz.) Baill.) sensitized Pgp-MDR HepG2-DR cells by interfering with the function of Pgp-substrate complexes. In Pgp-MDR cells, SCH enhanced the cytotoxicity of cancer drugs that are Pgp substrates and restored vinblastine-induced G2/M arrest without lowering Pgp expression. SCH increased cellular retention of Pgp substrates such as rhodamine 123. In Pgp-overexpressing membrane preparations, SCH stimulated basal Pgp-ATPase thus showing some substrate-like function. However, SCH was not a competitive inhibitor for verapamil or progesterone and decreased their Km. In the presence of substrates, SCH decreased the reactivity between Pgp and the monoclonal antibody UIC-2 which is normally increased with active substrate-Pgp complexes. The labeling of active Pgp transport sites by [125I]-iodoarylazidoprazosin was partially blocked by SCH. SCH did not affect the activity of the mutant Pgp F983A suggesting that SCH acted differently than the thioxanthene type of Pgp allosteric inhibitors. Our results suggest that SCH acts by affecting the normal formation and functioning of the Pgp-substrate complexes.

PMID: 17318783 [PubMed - indexed for MEDLINE]

[Prognostic analysis of stage III-IV non-small cell lung cancer patients treated by traditional chinese medicine]

Site Editor — Fri, 13 Jul 2007 18:24:04 -0700

[Prognostic analysis of stage III-IV non-small cell lung cancer patients treated by traditional chinese medicine]: Ai Zheng. 2005 Oct;24(10):1252-6 Authors: Zhou DH, Lin LZ, Zhou YQ, Luo RC, Liu KF, Jia YJ, Chen JY, Niu XW, Su BR, Lu J, Wang ST

BACKGROUND & OBJECTIVE: Chemotherapy is a treatment for stage III-IV non-small cell lung cancer (NSCLC), but the efficacy is not ideal. Traditional Chinese medicine (TCM) has certain effect on NSCLC. This study was to investigate various factors that affect the prognosis of advanced NSCLC, and evaluate the role of TCM in enlonging survival time of patients with stage III-IV NSCLC. METHODS: The NSCLC patients who meet the inclusive criteria were randomized into TCM group, combination (TCM plus NP regimen) group, and chemotherapy group, and received relevant treatments. The median survival time (MST) was calculated by Kaplan-Meier method. The prognosis of the patients was analyzed by COX regression method. RESULTS: A total of 294 stage III-IV NSCLC patients were enrolled, of which 99 were in TCM group, 103 in combination group, 92 in chemotherapy group. The MST were 292 days in TCM group, 355 days in combination group, and 236 days in chemotherapy group; the cumulative survival rates were 45.38%, 48.86%, and 42.17%, respectively (P>0.05). Cox regression analysis indicated that therapy, gender, disease course, erythrocyte sedimentation, KPS score, tumor size, and patient's weight were independent prognostic factors of stage III-IV NSCLC. CONCLUSION: Compare with chemotherapy alone, TCM combined with chemotherapy may prolong the survival time of stage III-IV NSCLC patients.

PMID: 16219143 [PubMed - indexed for MEDLINE]

Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence.

Site Editor — Fri, 13 Jul 2007 18:22:25 -0700

Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence.: Cancer Lett. 2007 Jun 18;251(1):43-52 Authors: Ye B, Aponte M, Dai Y, Li L, Ho MC, Vitonis A, Edwards D, Huang TN, Cramer DW

There is considerable interest in herbal therapies for cancer prevention but often with little scientific evidence to support their use. In this study, we examined epidemiological data regarding effects of commonly used herbal supplements on risk for ovarian cancer and sought supporting biological evidence. 4.2% of 721 controls compared to 1.6% of 668 cases regularly used Ginkgo biloba for an estimated relative risk (and 95% confidence interval) of 0.41 (0.20,0.84) (p=0.01); and the effect was most apparent in women with non-mucinous types of ovarian cancer, RR=0.33 (0.15,0.74) (p=0.007). In vitro experiments with normal and ovarian cancer cells showed that Ginkgo extract and its components, quercetin and ginkgolide A and B, have significant anti-proliferative effects ( approximately 40%) in serous ovarian cancer cells, but little effect in mucinous (RMUG-L) cells. For the ginkgolides, the inhibitory effect appeared to be cell cycle blockage at G0/G1 to S phase. This combined epidemiological and biological data provide supportive evidence for further studies of the chemopreventive or therapeutic effects of Ginkgo and ginkgolides on ovarian cancer.

PMID: 17194528 [PubMed - indexed for MEDLINE]

Selective killing of cancer cells by leaf extract of Ashwagandha: identification of a tumor-inhibitory factor [...]

Site Editor — Fri, 13 Jul 2007 18:13:04 -0700

Selective killing of cancer cells by leaf extract of Ashwagandha: identification of a tumor-inhibitory factor and the first molecular insights to its effect.: Clin Cancer Res. 2007 Apr 1;13(7):2298-306 Authors: Widodo N, Kaur K, Shrestha BG, Takagi Y, Ishii T, Wadhwa R, Kaul SC

PURPOSE: Ashwagandha is regarded as a wonder shrub of India and is commonly used in Ayurvedic medicine and health tonics that claim its variety of health-promoting effects. Surprisingly, these claims are not well supported by adequate studies, and the molecular mechanisms of its action remain largely unexplored to date. We undertook a study to identify and characterize the antitumor activity of the leaf extract of ashwagandha. EXPERIMENTAL DESIGN: Selective tumor-inhibitory activity of the leaf extract (i-Extract) was identified by in vivo tumor formation assays in nude mice and by in vitro growth assays of normal and human transformed cells. To investigate the cellular targets of i-Extract, we adopted a gene silencing approach using a selected small hairpin RNA library and found that p53 is required for the killing activity of i-Extract. RESULTS: By molecular analysis of p53 function in normal and a variety of tumor cells, we found that it is selectively activated in tumor cells, causing either their growth arrest or apoptosis. By fractionation, purification, and structural analysis of the i-Extract constituents, we have identified its p53-activating tumor-inhibiting factor as with a none. CONCLUSION: We provide the first molecular evidence that the leaf extract of ashwagandha selectively kills tumor cells and, thus, is a natural source for safe anticancer medicine.

PMID: 17404115 [PubMed - indexed for MEDLINE]

Induction of apoptosis by ginger in HEp-2 cell line is mediated by reactive oxygen species.

Site Editor — Fri, 13 Jul 2007 18:10:37 -0700

Induction of apoptosis by ginger in HEp-2 cell line is mediated by reactive oxygen species.: Basic Clin Pharmacol Toxicol. 2007 May;100(5):302-7 Authors: Vijaya Padma V, Arul Diana Christie S, Ramkuma KM

Ginger (Zingiber officinale Roscoe, Zingiberaceae) is a commonly used medicinal herb throughout the world. Although some studies have demonstrated its antitumour activities on cancer cells in vitro and in vivo, the exact mechanism is not fully elucidated. Hence, the present study was designed to examine the in vitro cytotoxic activities of saline extract prepared from ginger extract on HEp-2 cell line. The cytotoxic effect of the drug was confirmed by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and cell counting and estimation of protein, DNA and RNA. Meanwhile, propidium iodide staining and agarose gel electrophoresis were performed for determining the induction of apoptosis. In addition, superoxide radical generation, nitrite formation and glutathione studies show involvement of free radicals. The present results show that the extract exerts dose-dependent suppression of cell proliferation; the IC(50) value was found to be 900 microg/ml. At a dose of 250 microg/ml, marked morphological changes including cell shrinkage and condensation of chromosomes were observed. Agarose gel electrophoresis of DNA from HEp-2 cells treated with 250 microg/ml ginger powder for 24 hr showed marked DNA ladder pattern. The involvement of free radicals was confirmed by increased superoxide production, decreased nitrate formation and depletion of glutathione in ginger-treated cells. Further screening of active components using gas chromatography-mass spectrometry analyses showed the presence of clavatol, geraniol and pinostrobin in the extract. The results of the present study suggest that ginger might be useful as a potential antitumour agent.

PMID: 17448115 [PubMed - indexed for MEDLINE]

[Effects of phytoestrogens on prostate cancer and benign prostatic hyperplasia]

Site Editor — Fri, 13 Jul 2007 17:50:17 -0700

[Effects of phytoestrogens on prostate cancer and benign prostatic hyperplasia]: Zhonghua Nan Ke Xue. 2007 May;13(5):457-61 Authors: Feng Y, Xia XY, Huang YF

Phytoestrogens are non-steroidal estrogens widely distributed in many kinds of plants. They are natural compounds structurally similar to estrogen and with estrogenic or anti-androgenic activities. Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent and associated with age. Recently, in many epidemiological and experimental researches, it has been reported that phytoestrogens play a role in the prevention and treatment of PCa and BPH. Regulation of sexual hormones, inhibition of cell proliferation, induction of cell apoptosis and anti-oxidation of such plant estrogens may be involved in the mechanisms.

PMID: 17569267 [PubMed - in process]

[...] the growth stimulatory effect of soy and its isoflavones on established breast cancer

Site Editor — Sat, 23 Jun 2007 05:30:16 -0700

Can the combination of flaxseed and its lignans with soy and its isoflavones reduce the growth stimulatory effect of soy and its isoflavones on established breast cancer?:

Can the combination of flaxseed and its lignans with soy and its isoflavones reduce the growth stimulatory effect of soy and its isoflavones on established breast cancer?

Mol Nutr Food Res. 2007 Jun 20;

Authors: Power KA, Thompson LU

Consumption of phytoestrogen (PE)-rich foods (i. e., soy and flaxseed (FS)) is increasing because of their suggested health benefits. However, recent studies raise concern over the safety of soy and its isoflavones, particularly genistein (GEN), for postmenopausal breast cancer (BC), due to their potential stimulatory effects on human breast tissue and on the growth of existing tumors in rodents. FS, rich in PE lignans, which is metabolized to the mammalian lignans enterolactone (ENL) and enterodiol (END), has consistently been shown to have tumor inhibitory effects in a human clinical trial as well as rodent BC models. Using the preclinical athymic mouse postmenopausal BC model, combining FS with soy protein or GEN with END and ENL, was found to negate the tumor stimulatory effects of soy protein or GEN alone. The mechanism may be related to the modulation of estrogen receptor and MAPK signaling pathways. If these studies can be confirmed in clinical trials, then consumption of combined soy and FS, or their PEs, may reduce the tumor growth stimulatory effect of soy or GEN. This may indicate that if soy is consumed with lignan-rich foods, it may continue to induce its other beneficial health effects, without inducing adverse effect on postmenopausal BC.

PMID: 17579892 [PubMed - as supplied by publisher]

Effect of selected phytochemicals and apple extracts on NF-kappaB activation in human breast cancer MCF-7 cells.

Site Editor — Mon, 11 Jun 2007 06:01:47 -0700

Effect of selected phytochemicals and apple extracts on NF-kappaB activation in human breast cancer MCF-7 cells.: J Agric Food Chem. 2007 Apr 18;55(8):3167-73 Authors: Yoon H, Liu RH

Nuclear factor kappaB (NF-kappaB) is a transcription factor, which plays an important role in inflammation, cell proliferation, apoptosis, and immunity in eukaryotes. In cancer cells, NF-kappaB induces resistance to anticancer chemotherapeutic agents by increasing cell proliferation and inhibiting apoptosis. Therefore, inhibition of NF-kappaB activation in cancer cells is advantageous in cancer therapy by lowing the resistance to chemotherapy. Several phytochemicals from fruits and vegetables have been reported to inhibit NF-kappaB activation, but the mechanisms of how the phytochemicals work have not been fully understood. The present study examines the effects of selected phytochemicals and apple extracts on TNF-alpha-induced NF-kappaB activation in human breast cancer MCF-7 cells. Apple extracts significantly inhibited the TNF-alpha-induced NF-kappaB activation at a dose of 5 mg/mL (p < 0.05). Curcumin also significantly blocked the TNF-alpha-induced NF-kappaB activation at doses of 10 and 20 microM (p < 0.05). Neither apple extracts nor curcumin affected phosphorylation of inhibitor of NF-kappaB-alpha (IkappaB-alpha); both significantly inhibited proteasomal activity of MCF-7 cells at doses of 2.5 and 5 mg/mL of apple extracts and 20 microM of curcumin (p < 0.05). These results suggest that apple extracts and curcumin have the capabilities of inhibiting TNF-alpha-induced NF-kappaB activation of MCF-7 cells by inhibiting the proteasomal activities instead of IkappaB kinase (IKK) activation.

Study of the anticancer potential of Yemeni plants used in folk medicine.

Site Editor — Mon, 11 Jun 2007 05:48:39 -0700

Study of the anticancer potential of Yemeni plants used in folk medicine.: Pharmazie. 2007 Apr;62(4):305-7 Authors: Mothana RA, Grünert R, Lindequist U, Bednarski PJ

The present work evaluated the anticancer activity of methanol extracts from 24 plants used in Yemeni traditional medicine. To evaluate the in vitro cytotoxic potency of the investigated extracts, an established microtiter plate assay based on cellular staining with crystal violet was used with 5 human cancer cell lines: two lung cancer (A-427 and LCLC-103H), two urinary bladder carcinoma (5637 and RT-112) and one breast cancer (MCF-7) line. The methanolic extracts of Dendrosicyos socotrana, Withanina aduensis, Withania riebeckii, Dracena cinnabari and Buxus hildebrandtii exhibited the highest toxicity on all tumor cell lines with IC50 values ranging between 0.29 and 5.54 microg/ml. The extracts of Jatropha unicostata and Punica protopunica showed a moderate potency on the most tumor cell lines.

Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts.

Site Editor — Mon, 11 Jun 2007 05:43:57 -0700

Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts.: Eur J Med Res. 2007 Mar 26;12(3):103-19 Authors: Kienle GS, Kiene H

BACKGROUND: Anthroposophic Mistletoe therapy is a widely used complementary cancer treatment. OBJECTIVE: To evaluate prospective clinical trials on the effectiveness of anthroposophic mistletoe therapy for cancer. DESIGN: Systematic review. MATERIAL AND METHODS: Search of 9 electronic databases, reference lists and extensive expert consultations. Criteria-based assessment of methodological study quality. RESULTS: 16 randomized (RCT) and 9 non-randomized (N-RCT) controlled trials were identified that investigated mistletoe treatment of malignant diseases. Statistically significant benefit for survival was reported in 8 of 17 trials (in 5 of 10 RCTs), for disease-free survival and tumour recurrence in none of 2 RCTs, for remission of tumour and malignant effusion in 1 RCT and 1 N-RCT of 4 controlled trials, for quality of life (QoL) in 3 of 5 RCTs, and for QoL and reduction of side effects of cytoreductive therapies (chemotherapy, radiation or surgery) in 5 of 7 trials (3 of 5 RCTs). Methodological quality of the controlled trials differed substantially; some had major limitations while others were reasonably well conducted. 12 single-arm cohort studies were identified. 5 of 7 studies found substantial tumour remission in various cancers, one study reported remission of CIN, and 4 studies remission of malignant pleural effusion or ascites. Quality of reporting in cohort studies was mostly reasonably good. Mistletoe application was well tolerated. CONCLUSIONS: Regarding quality of studies and consistency of results, the best evidence for efficacy of mistletoe therapy exists for improvement of QoL and reduction of side effects of cytotoxic therapies (chemotherapy, radiation). Survival benefit has been shown but not beyond critique. Tumour remissions are described in cohort studies that investigate the application of high dose or local mistletoe extracts. As several reasonably well-conducted studies indicate beneficial effects, further properly designed trials should be encouraged to investigate clinical efficacy and its possible dependency on the mode of application.

Advances in the Use of Milk Thistle (Silybum marianum).

Site Editor — Mon, 11 Jun 2007 05:32:46 -0700

Advances in the Use of Milk Thistle (Silybum marianum).: Integr Cancer Ther. 2007 Jun;6(2):104-9 Authors: Post-White J, Ladas EJ, Kelly KM

Milk thistle (Silybum marianum) is an herbal supplement used to treat liver and biliary disorders. Silymarin, a mixture of flavanoid complexes, is the active component that protects liver and kidney cells from toxic effects of drugs, including chemotherapy. Although milk thistle has not significantly altered the course of chronic liver disease, it has reduced liver enzyme levels and demonstrated anti-inflammatory and T cell-modulating effects. There is strong preclinical evidence for silymarin's hepatoprotective and anticarcinogenic effects, including inhibition of cancer cell growth in human prostate, skin, breast, and cervical cells. Milk thistle is considered safe and well-tolerated, with gastrointestinal upset, a mild laxative effect, and rare allergic reaction being the only adverse events reported when taken within the recommended dose range. More clinical trials of rigorous methodology, using standardized and well-defined products and dosages, are needed to evaluate the potential of silymarin against liver toxicity, chronic liver disease, and human cancers.

Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies.

Site Editor — Mon, 11 Jun 2007 05:31:23 -0700

Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies.: Integr Cancer Ther. 2007 Jun;6(2):110-9 Authors: Kroll DJ, Shaw HS, Oberlies NH

Extracts of milk thistle have been recognized for centuries as "liver tonics" and are well-known to prevent or reverse hepatotoxicity of reactive drug metabolites or naturally occurring toxins. Milk thistle extracts are now under intense study in the experimental therapeutics of cancer for chemoprevention, treatment, and amelioration of chemotherapy side effects. Precision in nomenclature, however, has lagged behind this progress. The crude commercial product of milk thistle is termed silymarin, a complex of at least 7 flavonolignans and 1 flavonoid that comprises 65% to 80% of milk thistle extract. From silymarin is derived silibinin, a semipurified fraction once thought to be a single compound but now recognized as a 1:1 mixture of 2 diastereoisomers, silybin A and silybin B. The distinction between silymarin and silibinin is not only important to understanding the historical literature, but thorough characterization and use of chemically defined mixtures in preclinical and clinical studies are essential to the progress of these botanical compounds as human therapeutics. As a result, we urge clinicians and preclinical investigators alike to exercise rigor in nomenclature and use pure compounds or precisely defined chemical mixtures in subsequent studies. Herein, we provide a guide to the proper nomenclature and composition of milk thistle extracts and discuss the known pharmacokinetic studies of these botanical medicines. The drug-interaction potential of these extracts appears to be quite low, and in fact, silibinin appears to synergize with the antitumor effects of some commonly used chemotherapeutics. However, some precautions are advised as high-dose, phase II studies are conducted.

A routine experimental protocol for qHNMR illustrated with Taxol.

Site Editor — Wed, 30 May 2007 00:58:45 -0700

A routine experimental protocol for qHNMR illustrated with Taxol.: J Nat Prod. 2007 Apr;70(4):589-95 Authors: Pauli GF, Jaki BU, Lankin DC

Quantitative 1H NMR (qHNMR) provides a value-added dimension to the standard spectroscopic data set involved in structure analysis, especially when analyzing bioactive molecules and elucidating new natural products. The qHNMR method can be integrated into any routine qualitative workflow without much additional effort by simply establishing quantitative conditions for the standard solution 1H NMR experiments. Moreover, examination of different chemical lots of taxol (paclitaxel) and a Taxus brevifolia extract as working examples led to a blueprint for a generic approach to performing a routinely practiced 13C-decoupled qHNMR experiment and for recognizing its potential and main limitations. The proposed protocol is based on a newly assembled 13C GARP broadband decoupled proton acquisition sequence that reduces spectroscopic complexity by removal of carbon satellites. The method is capable of providing qualitative and quantitative NMR data simultaneously and covers various analytes from pure compounds to complex mixtures such as metabolomes. Due to a routinely achievable dynamic range of 300:1 (0.3%) or better, qHNMR qualifies for applications ranging from reference standards to biologically active compounds to metabolome analysis. Providing a "cookbook" approach to qHNMR, acquisition conditions are described that can be adapted for contemporary NMR spectrometers of all major manufacturers.

Inhibition of cancer cell proliferation and suppression of TNF-induced activation of NFkappaB by edible berry juice.

Site Editor — Fri, 25 May 2007 02:31:01 -0700

Inhibition of cancer cell proliferation and suppression of TNF-induced activation of NFkappaB by edible berry juice.: Anticancer Res. 2007 Mar-Apr;27(2):937-48 Authors: Boivin D, Blanchette M, Barrette S, Moghrabi A, Béliveau R

BACKGROUND: Berries contain several phytochemicals, such as phenolic acids, proanthocyanidins, anthocyanins and other flavonoids. There has been growing interest in a variety of potential chemopreventive activities of edible berries. The potential chemopreventive activity of a variety of small berries cultivated or collected in the province of Québec, Canada were evaluated here. MATERIALS AND METHODS: Strawberry, raspberry, black currant, red currant, white currant, gooseberry, high-bush blueberry, low-bush blueberry, velvet leaf blueberry, serviceberry, blackberry, black chokeberry, sea buckthorn and cranberry were evaluated for antioxidant capacity, anti-proliferative activity, anti-inflammatory activity, induction of apoptosis and cell cycle arrest. RESULTS: The growth of various cancer cell lines, including those of stomach, prostate, intestine and breast, was strongly inhibited by raspberry, black currant, white currant, gooseberry, velvet leaf blueberry, low-bush blueberry, sea buckthorn and cranberry juice, but not (or only slightly) by strawberry, high-bush blueberry, serviceberry, red currant, or blackberry juice. No correlation was found between the anti-proliferative activity of berry juices and their antioxidant capacity (p > 0.05). The inhibition of cancer cell proliferation by berry juices did not involve caspase-dependent apoptosis, but appeared to involve cell-cycle arrest, as evidenced by down-regulation of the expression of cdk4, cdk6, cyclin D1 and cyclin D3. Of the 13 berries tested, juice of 6 significantly inhibited the TNF-induced activation of COX-2 expression and activation of the nuclear transcription factor NFkappaB. CONCLUSION: These results illustrate that berry juices have striking differences in their potential chemopreventive activity and that the inclusion of a variety of berries in the diet might be useful for preventing the development of tumors.

Medicinal herbs for esophageal cancer.

Site Editor — Fri, 25 May 2007 02:27:53 -0700

Medicinal herbs for esophageal cancer.: Cochrane Database Syst Rev. 2007;(1):CD004520 Authors: Taixiang W, Wei X, Yang X, Zhiyu C

BACKGROUND: Esophageal cancer is the seventh leading cause of cancer death worldwide. Traditional Chinese medicinal herbs are sometimes used as an adjunct to radiotherapy or chemotherapy for this type of cancer. OBJECTIVES: To assess the efficacy and possible adverse effects of the addition of Chinese medicinal herbs to treatment with radiotherapy or chemotherapy for esophageal cancer. SEARCH STRATEGY: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, The Cochrane Library, MEDLINE, EMBASE, AMED (Allied and Complementary Medicine Database), CBM (Chinese Biomedical Database), China National Knowledge Infrastructure, the Chinese Cochrane Centre Controlled Trials Register and CISCOM (The Research Council for Complementary Medicine) (up to June 2004). Databases of ongoing trials, the internet and reference lists were also searched. SELECTION CRITERIA: Randomised controlled trials comparing the use of radiotherapy or chemotherapy with and without the addition of Chinese medicinal herbs. DATA COLLECTION AND ANALYSIS: At least two review authors extracted data and assessed trial quality. MAIN RESULTS: Two studies were included. The numbers of participants in these two trials were 42 and 80, 122 in total. Both studies were analysed separately because of the differences in interventions used. Although one study reported a positive result, the majority of outcome measurements from the two studies showed no significant benefit with the addition of Chinese herbal medicines to radiotherapy or chemotherapy. There was statistically significant improvement in quality of life with the additional Huachansu injection, however, no statistically significant improvement was found in short-term therapy effects, one-year survival rate or the adverse effect of radiation-induced esophagitis. AUTHORS' CONCLUSIONS: The included studies were of low quality. The results suggest Zhenxiang capsules or Huachansu injection may not improve short-term therapy effects or one-year survival rate when used as adjunct treatment to chemo- or radiotherapy in the treatment of esophageal cancer. The quality of life may be improved by Huachansu injection. The results suggest that more high-quality trials on Huachansu injection and other Chinese herbal medicines are needed in the future.

Gene expression analysis of the mechanisms whereby black cohosh inhibits human breast cancer cell growth.

Site Editor — Fri, 11 May 2007 15:55:23 -0700

Gene expression analysis of the mechanisms whereby black cohosh inhibits human breast cancer cell growth.: Anticancer Res. 2007 Mar-Apr;27(2):697-712 Authors: Einbond LS, Su T, Wu HA, Friedman R, Wang X, Jiang B, Hagan T, Kennelly EJ, Kronenberg F, Weinstein IB

BACKGROUND: Previous studies indicate that specific extracts and the pure triterpene glycoside actein obtained from black cohosh inhibit growth of human breast cancer cells. Our aim is to identify alterations in gene expression induced by treatment with a methanolic extract (MeOH) of black cohosh. MATERIALS AND METHODS: We treated MDA-MB-453 human breast cancer cells with the MeOH extract at 40 microg/ml and collected RNA at 6 and 24 h; we confirmed the microarray results with real-time RT-PCR for 18 genes. RESULTS: At 6 h after treatment there was significant increase in expression of ER stress (GRP78), apoptotic (GDF15), lipid biosynthetic (INSIG1 and HSD17B7) and Phase 1 (CYP1A1) genes and, at 24 h, decrease in expression of cell cycle (HELLS and PLK4) genes. CONCLUSION: Since the MeOH extract activated genes that enhance apoptosis and repressed cell cycle genes, it may be useful in the prevention and therapy of breast cancer.

Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds.

Site Editor — Fri, 11 May 2007 15:52:33 -0700

Evidence for the involvement of carbon-centered radicals in the induction of apoptotic cell death by artemisinin compounds.: J Biol Chem. 2007 Mar 30;282(13):9372-82 Authors: Mercer AE, Maggs JL, Sun XM, Cohen GM, Chadwick J, O'Neill PM, Park BK

Artemisinin and its derivatives are currently recommended as first-line antimalarials in regions where Plasmodium falciparum is resistant to traditional drugs. The cytotoxic activity of these endoperoxides toward rapidly dividing human carcinoma cells and cell lines has been reported, and it is hypothesized that activation of the endoperoxide bridge by an iron(II) species, to form C-centered radicals, is essential for cytotoxicity. The studies described here have utilized artemisinin derivatives, dihydroartemisinin, 10beta-(p-bromophenoxy)dihydroartemisinin, and 10beta-(p-fluorophenoxy)dihydroartemisinin, to determine the chemistry of endoperoxide bridge activation to reactive intermediates responsible for initiating cell death and to elucidate the molecular mechanism of cell death. These studies have demonstrated the selective cytotoxic activity of the endoperoxides toward leukemia cell lines (HL-60 and Jurkat) over quiescent peripheral blood mononuclear cells. Deoxy-10beta-(p-fluorophenoxy)dihydroartemisinin, which lacks the endoperoxide bridge, was 50- and 130-fold less active in HL-60 and Jurkat cells, respectively, confirming the importance of this functional group for cytotoxicity. We have shown that chemical activation is responsible for cytotoxicity by using liquid chromatography-mass spectrometry analysis to monitor endoperoxide activation by measurement of a stable rearrangement product of endoperoxide-derived radicals, which was formed in sensitive HL-60 cells but not in insensitive peripheral blood mononuclear cells. In HL-60 cells the endoperoxides induce caspase-dependent apoptotic cell death characterized by concentration- and time-dependent mitochondrial membrane depolarization, activation of caspases-3 and -7, sub-G(0)/G(1) DNA formation, and attenuation by benzyloxycarbonyl-VAD-fluoromethyl ketone, a caspase inhibitor. Overall, these results indicate that endoperoxide-induced cell death is a consequence of activation of the endoperoxide bridge to radical species, which triggers caspase-dependent apoptosis.