Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters

Molecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells.     

Pulmonary carcinosarcoma with an osteosarcomatous component

Pulmonary carcinosarcoma is a rare disease entity defined as a neoplasm, which has biphasic features consisting of both epithelial and sarcomatous components. It has been reported that the most frequent epithelial component is squamous cell carcinoma, while the most frequent sarcomatous component is rhabdomyosarcoma. Pulmonary carcinosarcomas with osteosarcoma components are even rarer. We report a case of a potentially curative resection for carcinosarcoma with an osteosarcoma component. Thoracic surgeons should be aware of this rare tumor when lung tumors with ossification are encountered.     

Estimation of the timing of carotid artery flow using peripheral pulse wave-gated MRI

Purpose:

To investigate the relationship between peripheral pulse wave (PPW)‐gating and the carotid systolic pulse wave in a large clinical patient cohort, and to establish a process for correct estimation of delay time from PPW‐gating to foot (ie, beginning) or peak times of carotid systolic pulse waves.

Materials and Methods:

Subjects comprised 209 patients scanned using 3T magnetic resonance imaging (MRI) for PPW‐gated phase contrast images at the common carotid artery. Stepwise multiple regression analysis was conducted for the relationship between foot or peak times and the following factors after excluding correlated factors with coefficients ≥0.5: pulse rate (PR); systolic blood pressure; diastolic blood pressure; height; body weight; body mass index; Brinkman index; diabetes mellitus; hypertension; and hyperlipidemia.

Results:

PR showed significant correlation with foot (r = ?0.86, P < 0.001) and peak (r = ?0.87, P < 0.001) times. The following equations were derived: foot time (msec) = ?8.55 × PR + 993.1 and peak time (msec) = ?9.21 × PR + 1142.3. No other factors showed significant correlations.

Conclusion:

PR was the only factor showing significant relationships to foot and peak times of carotid artery flow. The derived equations will facilitate various kinds of noncontrast MR acquisition with simple PPW‐gating. J. Magn. Reson. Imaging 2012;36:454–458. © 2012 Wiley Periodicals, Inc.

     

Guidewire bias in rotational atherectomy in the angled lesion: evaluation based on the thickness of the ablated intima and media.

The effect of guidewire bias on angled-lesion ablation by rotational atherectomy (RA) was assessed by measuring the changes in vertical lumen diameter, horizontal lumen diameter and the intima-media thickness of the coronary artery, using intravascular ultrasound in 10 lesions with an angle greater than 10 degrees. The vertical and horizontal diameters significantly increased after RA. The intima-media thickness at the 4 orthogonal sites significantly decreased. There was a significant positive correlation between vertical diameter change and angle (r=0.642, p=0.045), but none between horizontal diameter change and angle. There was no correlation between intima-media thickness change at 0 degrees and angle; however, at 180 degrees there was a tendency to correlation with angle (r=0.602, p=0.066). These data suggest that in cases of angled lesions, the increase in vertical lumen diameter is caused more by ablation of the 180 degrees wall than by that of the 0 degrees wall, which is brought about by guidewire bias toward the vascular wall at 180 degrees.     

Therapeutic advances in BIG3‐PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer

Our previous studies demonstrated that specific inhibition of the BIG3‐PHB2 complex, which is a critical modulator in estrogen (E2) signaling, using ERAP, a dominant negative peptide inhibitor, leads to suppression of E2‐dependent estrogen receptor (ER) alpha activation through the reactivation of the tumor suppressive activity of PHB2. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the crosstalk between E2 and growth factors associated with intrinsic or acquired resistance to anti‐estrogen tamoxifen in breast cancer cells. Intrinsic PHB2 released from BIG3 by ERAP effectively disrupted each interaction of membrane‐associated ERα and insulin‐like growth factor 1 receptor beta (IGF‐1Rβ), EGFR, PI3K or human epidermal growth factor 2 (HER2) in the presence of E2 and the growth factors IGF or EGF, followed by inhibited the activation of IGF‐1Rβ, EGFR or HER2, and reduced Akt, MAPK and ERα phosphorylation levels, resulting in significant suppression of proliferation of ERα‐positive breast cancer cells in vitro and in vivo. More importantly, combined treatment with ERAP and tamoxifen led to a synergistic suppression of signaling that was activated by crosstalk between E2 and growth factors or HER2 amplification. Taken together, our findings suggest that the specific inhibition of BIG3‐PHB2 is a novel potential therapeutic approach for the treatment of tamoxifen‐resistant breast cancers activated by the crosstalk between E2 and growth factor signaling, especially in premenopausal women.