Future opportunities in preventing cisplatin induced ototoxicity

Cisplatin is one of the most commonly used cytotoxic agents. Ototoxicity is an important and dose-limiting side-effect of cisplatin therapy. It is believed that cisplatin suppresses the formation of endogenous anti-oxidants that normally prevent the inner ear against reactive oxygen species (ROS). These ROS affect the outer hair cells (OHCs) in the organ of Corti. Results from clinical trials with amifostine, an anti-oxidant with possible otoprotective action during cisplatin therapy, were disappointing. A variety of agents with chemoprotective action against cisplatin-induced ototoxicity were successfully tested in animal models. It is important to translate these promising results from animal models into clinical practice. The possible routes of administration are systemic and transtympanic. An important condition when using such an agent systemically is that the compound may not affect the anti-tumor effect of cisplatin. The critical step at transtympanic administration is the diffusion of the compound through the round window membrane (RWM). This diffusion depends on the characteristics of the medication as on the properties of the RWM. Positive results of an otoprotector in clinical practice may increase the effectiveness of cisplatin therapy and can improve the quality of life for a large group of patients.     

Caffeic acid phenethyl ester profoundly modifies protein synthesis profile in type 5 adenovirus-transformed cloned rat embryo fibroblast cells

Caffeic acid phenethyl ester (CAPE), an active component of propolis from bee hives, exerts a plethora of biological changes in diverse systems. These include antimitogenic, anticarcinogenic, anti-inflammatory and immunomodulatory responses. CAPE directly induces programmed cell death (apoptosis) in type 5 adenovirus (Ad5)-transformed cloned rat embryo fibroblast cells, wt3A. To identify the gene and protein expression changes induced by CAPE in wt3A cells we used a strategy involving in vitro translation of mRNAs followed by high resolution two-dimensional (2D) gel electrophoresis. This approach results in the detection of 745 spots, including 172 displaying differences in expression upon exposure to CAPE. A high proportion of spots show profound changes in spot intensity (42 spots with increased and 27 spots with decreased intensity) following CAPE treatment. These studies provide a basis for comparing these changes to known protein patterns of various cell populations with an ultimate aim of identifying families of polypeptides responsible for the up- and down-regulation of cellular proteins during CAPE-induced apoptosis. Specific newly appearing or completely disappearing spots (52 and 51 molecular species, respectively) will be used to attempt to identify and retrieve their cDNA counterparts from an ordered cDNA library. These approaches represent a novel strategy for cloning genes associated with and potentially mediating apoptosis.     

Caffeic acid phenethyl ester preferentially sensitizes CT26 colorectal adenocarcinoma to ionizing radiation without affecting bone marrow radioresponse

PURPOSE: Caffeic acid phenethyl ester (CAPE), a component of propolis, was reported capable of depleting glutathione (GSH). We subsequently examined the radiosensitizing effect of CAPE and its toxicity. METHODS AND MATERIALS: The effects of CAPE on GSH level, GSH metabolism enzyme activities, NF-kappaB activity, and radiosensitivity in mouse CT26 colorectal adenocarcinoma cells were determined. BALB/c mouse with CT26 cells implantation was used as a syngeneic in vivo model for evaluation of treatment and toxicity end points. RESULTS: CAPE entered CT26 cells rapidly and depleted intracellular GSH in CT26 cells, but not in bone marrow cells. Pretreatment with nontoxic doses of CAPE significantly enhanced cell killing by ionizing radiation (IR) with sensitizer enhancement ratios up to 2.2. Pretreatment of CT26 cells with N-acetyl-L-cysteine reversed the GSH depletion activity and partially blocked the radiosensitizing effect of CAPE. CAPE treatment in CT26 cells increased glutathione peroxidase, decreased glutathione reductase, and did not affect glutathione S-transferase or gamma-glutamyl transpeptidase activity. Radiation activated NF-kappaB was reversed by CAPE pretreatment. In vivo study revealed that pretreatment with CAPE before IR resulted in greater inhibition of tumor growth and prolongation of survival in comparison with IR alone. Pretreatment with CAPE neither affected body weights nor produced hepatic, renal, or hematopoietic toxicity. CONCLUSIONS: CAPE sensitizes CT26 colorectal adenocarcinoma to IR, which may be via depleting GSH and inhibiting NF-kappaB activity, without toxicity to bone marrow, liver, and kidney.     

Caffeic acid phenethyl ester decreases cholangiocarcinoma growth by inhibition of NF‐κB and induction of apoptosis

Caffeic acid phenethyl ester (CAPE) inhibits the growth of tumor cells and is a known inhibitor of nuclear factor kappa beta (NF‐κB), which is constitutively active in cholangiocarcinoma (CCH) cells. We evaluated the effects of CAPE on CCH growth both in vitro and in vivo. Inhibition of NF‐κB DNA‐binding activity was confirmed in nuclear extracts treated with CAPE at 50, 40 and 20 μM. CAPE decreases the expression of NF‐κB1 (p50) and RelA (p65). CAPE decreased the growth of a number of CCH cells but not normal cholangiocytes. Cell cycle decrease was seen by a decrease in PCNA protein expression and the number of BrdU‐positive cells treated with CAPE at 20 μM compared to vehicle. Inhibition of growth and increased cell cycle arrest of Mz‐ChA‐1 cells by CAPE were coupled with increased apoptosis. Bax expression was increased, whereas Bcl‐2 was decreased in cells treated with CAPE compared to vehicle. In vivo studies were performed in BALB/c nude (nu/nu) mice implanted subcutaneously with Mz‐ChA‐1 cells and treated with daily IP injections of DMSO or CAPE (10 mg/kg body weight in DMSO) for 77 days. Tumor growth was decreased and tumor latency was increased 2‐fold in CAPE compared to vehicle‐treated nude mice. In tumor samples, decreased CCH growth by CAPE was coupled with increased apoptosis. CAPE both in vivo and in vitro decreases the growth of CCH cells by increasing apoptosis. These results demonstrate that CAPE might be an important therapeutic tool in the treatment of CCH. © 2009 UICC     

Antiproliferation and radiosensitization of caffeic acid phenethyl ester on human medulloblastoma cells

Purpose: To investigate antiproliferative and radiosensitizing effects of caffeic acid phenethyl ester (CAPE) on medulloblastoma (MB) Daoy cells. Methods and materials: Daoy cells were treated with CAPE in different concentrations and assessed for cell viability, apoptosis, cell cycles, cyclin B1 expressions, radiosensitization and chemosensitization. Human astroglia SVGp12 cells were treated with CAPE to present the possible protection or complication effects in normal tissues. Results: CAPE inhibited the growth of Daoy cells in a time- and concentration-dependent manner in MTT and Trypan blue exclusion assays. Flow cytometry revealed that CAPE significantly decreased G2/M fraction, and increased the S phase fraction. Western blot demonstrated a down-regulated cyclin B1 protein expression. Pretreatment with CAPE markedly decreased the viability of irradiated Daoy cells. The sensitizer enhancement ratios (SERs) were increased in CAPE-treated Daoy cells. CAPE in doxorubicin and cisplatin did not show chemosensitizing effect. Conclusions: These findings demonstrate the antiproliferative and radiosensitizing effects of CAPE for Daoy cells, which might bring improvement to the treatment of MB. For clinical application, in vivo models are expected.     

Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral cancer cells

As part of our previous search for new compounds with improved biological activities including antibiotic, antiviral, anti-inflammatory, and tumor growth inhibition activities, we synthesized some caffeic acid phenethyl ester (CAPE)-like compounds from commercially available caffeic acid. Nine chemicals were tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on the growth of buccal mucosal fibroblast (BF), oral submucosus fibroblast (OSF), neck metastasis of Gingiva carcinoma (GNM), and tongue squamous cell carcinoma (TSCCa) cells. CAPE and its ethyl analogue show significant cytotoxicity on OSF, GNM, and TSCCa cells, but not on BF cells. The results suggest that CAPE-like compounds may be potential chemotherapy agents against oral cancer.     

Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1

Prostate cancer (PCa) patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer (CRPC) within 1–3 years. Treatment with caffeic acid phenethyl ester (CAPE) suppressed cell survival and proliferation via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4–2 CRPC cells. CAPE treatment also inhibited soft agar colony formation and retarded nude mice xenograft growth of LNCaP 104-R1 cells. We identified that CAPE treatment significantly reduced protein abundance of Skp2, Cdk2, Cdk4, Cdk7, Rb, phospho-Rb S807/811, cyclin A, cyclin D1, cyclin H, E2F1, c-Myc, SGK, phospho-p70S6kinase T421/S424, phospho-mTOR Ser2481, phospho-GSK3α Ser21, but induced p21^Cip1, p27^Kip1, ATF4, cyclin E, p53, TRIB3, phospho-p53 (Ser6, Ser33, Ser46, Ser392), phospho-p38 MAPK Thr180/Tyr182, Chk1, Chk2, phospho-ATM S1981, phospho-ATR S428, and phospho-p90RSK Ser380. CAPE treatment decreased Skp2 and Akt1 protein expression in LNCaP 104-R1 tumors as compared to control group. Overexpression of Skp2, or siRNA knockdown of p21^Cip1, p27^Kip1, or p53 blocked suppressive effect of CAPE treatment. Co-treatment of CAPE with PI3K inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 or Bcl-2 inhibitor ABT737 showed synergistic suppressive effects. Our finding suggested that CAPE treatment induced cell cycle arrest and growth inhibition in CRPC cells via regulation of Skp2, p53, p21^Cip1, and p27^Kip1.     

Effects of indole-3-carbinol and phenethyl isothiocyanate on colon carcinogenesis induced by azoxymethane in rats

Indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC) are breakdown products of the glucosinolates glucobrassicin and gluconasturtiin, respectively, and are thought to reduce carcinogen activation by P450 enzymes. To assess the effects of these compounds on colon cancer risk, rats were divided into five groups and fed the following diets: control diet (AIN-93G), or diets with PEITC or I3C added to the control diet: high-PEITC (3.37 mmols/kg diet-high level of PEITC), low-PEITC (0.67 mmols/kg-low level of PEITC), high-I3C (6.8 mmols/kg-high level of I3C) and low-I3C (1.36 mmols/kg-low level of I3C). Diets were fed for 2 weeks before and 10 weeks after administration of the colon carcinogen azoxymethane. Precancerous lesion (aberrant crypt foci, ACF) number in the distal colon was significantly lower in both high-I3C and low-I3C groups (6.9 +/- 0.8 and 5.9 +/- 0.59 per cm2, respectively) when compared with the control group (10.4 +/- 0.9). No significant difference in ACF number was found between the PEITC group and the control group. ACF expressing sialomucin, thought to indicate ACF more likely to progress to tumors, were greater in the high-PEITC group (13 +/- 3) than the control (5.6 +/- 2). Mucin-depleted ACF, suggested to have the greatest tumorigenic potential, tended to be lower in the low-I3C group (P < 0.06) compared with the control group. Mucosal apoptotic and cell proliferation labeling indices did not differ among groups, suggesting that reduction in the ACF number by I3C does not involve alterations in mucosal cell kinetics. No significant differences were found among the groups in hepatic cytochrome P450 2E1 (CYP2E1) activity, the first enzyme involved in activation of azoxymethane. However, there was increased activity of NADPH- and NADH reductases with high-I3C, which are the enzymes involved in the transfer of reducing equivalents to cytochrome P450. These results suggest that I3C lowers colon cancer risk through a mechanism not involving reduction of carcinogen activation by CYP2E1.     

Expression of the transformed phenotype induced by diverse acting viral oncogenes mediates sensitivity to growth suppression induced by caffeic Acid phenethyl ester (cape)

Caffeic acid phenethyl ester (CAPE) displays enhanced growth suppressive and toxic effects toward cloned rat embryo fibroblast (CREF) cells transformed by adenovirus type 5 (Ad5) or the Ad5 E1A transforming gene versus untransformed CREF cells (Su et al, Mol Carcinogen 4: 231-242, 1991). The present study was conducted to determine if transformation of CREF cells with additional oncogenes rendered these cells sensitive to the antiproliferative effect of CAPE. Additionally, studies were conducted to determine if reversion of the transformed phenotype could modify CAPE sensitivity. CAPE displayed increased growth suppressive activity toward CREF cells transformed by a number of oncogenes, including Ha-ras, v-src, v-raf, human papillomavirus type 18 (HPV-18) and human papillomavirus type 51 (HPV-51). Employing Ha-ras-transformed CREF (Ha-ras) and Ha-ras-transformed CREF cells overexpressing the Krev-1 suppressor gene (Ha-ras/Krev-1), evidence for a direct relationship between expression of the transformed phenotype and CAPE sensitivity was demonstrated. Ha-ras/Krev-1 cells displaying a suppression of the transformed phenotype exhibited increased resistance to CAPE-induced growth suppression versus Ha-ras cells, whereas Ha-ras/Krev-1 cells escaping transformation-suppression following in vivo growth in nude mice displayed enhanced sensitivity to growth-suppression induced by CAPE. Similarly, mutant Ad5 (H5hr1)-transformed and v-src-transformed CREF cells displaying a stable reversion in transformation also displayed a reduced sensitivity to CAPE versus their transformed counterparts. These observations indicate a direct relationship between expression of the transformed phenotype and CAPE sensitivity. Elucidation of the mechanism by which CAPE selectively inhibits growth of transformed cells should provide important insights into the critical molecular changes mediating expression of the transformed state and could help identify cellular targets for cancer therapy.     

雾化吸入顺铂对大鼠卵巢功能的损伤情况

目的:了解雾化吸入顺铂对大鼠卵巢功能的损伤情况,同时探讨活性炭口罩是否对顺铂具有防护作用。方法:将60只成年雌性SD大鼠随机分为空白组、活性炭组、普通组及阳性组。空白组仅给予生理盐水雾化吸入,其余各组均给予顺铂2 mg/kg雾化吸入,每天一次,连续2个月。定期检测各组大鼠血清雌激素水平,在实验开始后第15天、30天、60天时取大鼠卵巢组织行病理切片观察。结果:在雾化早期,各组大鼠雌激素水平及卵巢组织病理均无明显变化。雾化60天时,各顺铂雾化组雌激素水平较前明显下降,卵巢组织病理呈现出卵巢体积缩小、卵泡闭锁增多及间质纤维化改变。结论:雾化吸入顺铂对大鼠卵巢功能有一定损害,这种损害随时间延长呈进行性加重。活性炭口罩对雾化顺铂所致卵巢功能损伤防护作用不明显。     

Amelioration of docetaxel/cisplatin induced polyneuropathy by alpha-lipoic acid.

Docetaxel (Taxotere^®; Aventis, Strasbourg, France) is currentlyconsidered to be one of the most important anticancer drugs.It is a semi-synthetic agent derived from baccatin III extractedfrom renewable Taxus baccata needles, which binds to tubulininducing its polymerization [1]. It inhibits cell replicationand leads to apoptosis. Docetaxel has displayed significantantitumor activity against non-small-cell lung cancer (NSCLC),head and     

Enhancement by tyrosine methyl ester of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats

The effect of tyrosine methyl ester (TME) on the incidence, number, and histological types of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in male Wistar rats. Rats were subcutaneously given TME, 512 mg/kg body weight, every other day after 20 weeks of oral treatment with MNNG. Prolonged alternate-day administration of TME caused a significant increase in the incidence and number of gastric cancers of the glandular stomach by week 52. However, it did not affect the histology of the cancers. TME also caused a significant increase in tissue norepinephrine concentrations in the antral portion of the gastric wall and in the labelling indices of the antral epithelial cells. However, TME had no influence on the serum gastrin level and antral pH. These findings indicate that TME enhances gastric carcinogenesis, and this may be related to its effects on increasing norepinephrine levels in the gastric wall and stimulating proliferation of the antral epithelial cells.     

Recovery of hearing following cisplatin ototoxicity in the guinea pig

BACKGROUND: To report a spontaneous recovery of hearing, following cisplatin ototoxicity in the guinea pig. The findings are related to the animal and human literature on recovery from hearing loss following cisplatin ototoxicity. MATERIALS AND METHODS: Hearing was measured from compound action potentials (CAP) evoked by acoustic tones, which were monitored daily from an electrode implanted onto the round window of the inner ear. Cisplatin was administered at 2 mg/kg/day intraperitoneally until a hearing loss occurred. RESULTS: A hearing loss occurred suddenly across the frequency range and recovered over the period 2-14 days after treatment. The endocochlear potential was significantly lower than normal before hearing recovery and normal following recovery. CONCLUSION: These findings suggest a pivotal role for the endocochlear potential in the hearing loss from cisplatin ototoxicity and its recovery, and a plausible mechanism for the hearing recovery sometimes reported in patients following cisplatin ototoxicity.     

N-acetyl cysteine and caffeic acid phenethyl ester sensitize astrocytoma cells to Fas-mediated cell death in a redox-dependent manner

In this study, we investigated the role of reactive oxygen species (ROS) in Fas-induced cell death in human astrocytoma cells. Fas activation increased intracellular ROS levels in a NADPH oxidase- and caspase-dependent manner. ROS inhibitors such as N-acetyl cysteine (NAC) and caffeic acid phenethyl ester (CAPE) dramatically sensitized astocytoma cells to Fas-induced loss of mitochondrial transmembrane potential and subsequent cell death, which were abrogated by pretreatment with z-VAD-fmk, a broad-spectrum caspase inhibitor. These results collectively indicate that NAC and CAPE sensitize astrocytoma cells to Fas-induced apoptosis in a redox-dependent manner, suggesting a potential use in the treatment of malignant brain tumors.