Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment.

BACKGROUND: Bortezomib is a proteasome inhibitor with minimal clinical activity as a monotherapy in solid tumours, but its combination with other targeted therapies is being actively investigated as a way to increase its anticarcinogenic properties. Here, we evaluate the therapeutic potential of co-treatment with bortezomib and indole-3-carbinol (I3C), a natural compound found in cruciferous vegetables, in human ovarian cancer. METHODS: We examined the effects of I3C, bortezomib and cisplatin in several human ovarian cancer cell lines. Synergy was determined using proliferation assays and isobologram analysis. Cell cycle and apoptotic effects were assessed by flow cytometry. The mechanism of I3C and bortezomib action was determined by RNA microarray studies, quantitative RT-PCR and western blotting. Antitumour activity of I3C and bortezomib was evaluated using an OVCAR5 xenograft mouse model. RESULTS: I3C sensitised ovarian cancer cell lines to bortezomib treatment through potent synergistic mechanisms. Combination treatment with bortezomib and I3C led to profound cell cycle arrest and apoptosis as well as disruptions to multiple pathways, including those regulating endoplasmic reticulum stress, cytoskeleton, chemoresistance and carcinogen metabolism. Moreover, I3C and bortezomib co-treatment sensitised ovarian cancer cells to the standard chemotherapeutic agents, cisplatin and carboplatin. Importantly, in vivo studies demonstrated that co-treatment with I3C and bortezomib significantly inhibited tumour growth and reduced tumour weight compared with either drug alone. CONCLUSION: Together, these data provide a novel rationale for the clinical application of I3C and bortezomib in the treatment of ovarian cancer.

Predictors of invasive adenocarcinoma after conization for cervical adenocarcinoma in situ.

OBJECTIVE: Modified radical hysterectomy has been advocated for the definitive treatment of patients with cervical adenocarcinoma in situ (ACIS) with positive conization margins due to the risk of a co-existing invasive cervical adenocarcinoma (ICA). We sought to identify patients who can be safely managed with an extrafascial hysterectomy based on predictors of invasion in the conization specimen. METHODS: Between 1996 and 2010, we identified 33 patients who had definitive surgical management for cervical ACIS following conization with positive margins and/or positive endocervical curettage (ECC). Demographic and pathologic characteristics were collected by chart review. Statistical analysis was performed using Fisher's exact test. RESULTS: Among 33 patients, 4 (12%) had ICA in the hysterectomy specimen. Predictors of ICA included pathologic suspicion of invasion (PSI) in the conization specimen and positive ECC. In patients with ICA at hysterectomy, PSI and ACIS-positive ECC were found in 75% (p=0.32) and 100% (p=0.09) respectively. When PSI was present and the ECC was positive, the positive predictive value (PPV) for ICA was 33% (2 of 6). When PSI was absent, the negative predictive value (NPV) for ICA was 94% (1 of 16). When both PSI and ECC were negative, the NPV for ICA was 100% (0 of 6). CONCLUSIONS: Women with cervical ACIS have the highest risk for ICA in the setting of positive cone margins, positive ECC, and presence of PSI in the conization specimen. Extrafascial hysterectomy remains a viable option for women with positive cone margins when ECC is negative and PSI is absent.

Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles.

OBJECTIVES.: The utility of hormone therapy in the management of uterine sarcomas is poorly defined. We hypothesize that estrogen receptor (ER) expression is common in uterine sarcomas, and carries prognostic significance. Further, we hypothesize that ER-positive uterine sarcomas respond to hormone therapy. METHODS.: We retrospectively reviewed charts of patients with uterine sarcomas. Stepwise Cox proportional hazards regression model was used to evaluate variables related to the risk of death: age, histology, stage, use of pelvic radiotherapy, and ER expression. In addition, we examined clinical outcomes in patients treated with aromatase inhibitors, megestrol acetate, depot medroxyprogesterone acetate, and tamoxifen. RESULTS.: Fifty-four patients underwent immunohistochemical staining, and 34 (63%) were ER-positive. Kaplan-Meier survival analysis and log-rank test indicated that patients with ER-positive sarcomas demonstrated improved overall survival when compared with ER-negative patients (median OS 36 vs. 16 months, p=0.004). Upon multivariate analysis, ER positivity retained significance as an independent predictor of survival (HR=0.32, CI 0.12-0.89, p=0.03). Four patients received hormonal treatment in the adjuvant setting and remained in remission (range of follow up: 18-68 months). Eighteen patients received hormone therapy in the setting of recurrent or progressive disease: fourteen (78%) demonstrated stable disease or complete or partial response (range of follow up: 6-124 months). CONCLUSIONS.: ER expression is common and is associated with improved overall survival in uterine sarcomas. Conducting immunohistochemical staining to ascertain ER status may aid with prognostication in this disease. Hormone therapy should be considered in patients with primary and recurrent ER-positive uterine sarcomas.

Effects of hydralazine on in vivo tumor energy metabolism, hematopoietic radiation sensitivity, and cardiovascular parameters.

Energy metabolism of murine FSaII foot tumors was studied by in vivo 31P-MRS in C3Hf/Sed mice. Spectroscopy was performed following exposure to escalating doses of hydralazine (HYD) ip. At 0.25 mg/kg, HYD caused a 20% increase in PCr/Pi and had no significant effect on mean arterial blood pressure. HYD doses greater than or equal to 2 mg/kg lead to hypotension which was associated with a decrease in PCr, NTP, pH, and an increase in Pi (p less than 0.01 for control vs 10 mg/kg HYD). When mice were given ip injections of HYD (0.25, 1, 2 and 10 mg/kg) 10 min prior to whole body irradiation, spleen stem cell survival after 6 Gy was increased (2.19 colonies in control animals vs 6.74 colonies per spleen in animals treated with greater than or equal to 2 mg/kg HYD), as was the LD50/30 dose (6.49 Gy [control] vs 9.00 Gy [10 mg/kg HYD]). The data provide evidence that PCr/Pi is a useful indicator of perfusion efficiency (and indirectly of hypoxic cell fraction) in FSaII tumors. These observations suggest that HYD may be a useful adjuvant for hyperthermic treatment of tumors and for potentiation of agents specifically toxic to hypoxic or nutrient-deprived cancer cells. HYD should be used with care in patients receiving radiation treatments or other therapies for which hypoxia can unfavorably affect treatment outcome.

Measurement of Indole-3-Acetic Acid in Peach Fruits (Prunus persica L. Batsch cv Redhaven) during Development.

The amount of indole-3-acetic acid (IAA) was measured in peach fruits by gas chromatography-mass spectrometry-selective ion monitoring using an isotope dilution assay with [(13)C(6)]IAA as an internal standard throughout the growing season. Ethylene evolution of the fruit was also measured. IAA levels were 25 nanograms per gram fresh weight, 18 days after anthesis. Both IAA levels and rates of ethylene evolution declined to their lowest levels (7 nanograms IAA per gram fresh weight and 0.01 nanoliter ethylene per gram per hour) in the second stage of fruit growth. Endogenous levels of free-IAA and ethylene evolution increased in the last stage of peach fruit development to 32 nanograms per gram fresh weight and 0.27 nanoliter per gram per hour, respectively. IAA amounts peaked in the ovules 67 days after anthesis.