Anti-proliferating and apoptosis-inducing activity of chemical compound FTI-6D in association with p53 in human cancer cell lines.

Compounds with 3,4-fused tricyclic indole (FTI) frameworks are attractive scaffolds for drug discovery. We synthesized FTI-6D, a compound with this framework, which was cytotoxic in several human cancer cell lines. FTI-6D induced apoptosis via activation of the p53 downstream mitochondria-related apoptotic pathway, characterized by an increased ratio of pro-apoptotic Bcl-2 family members to anti-apoptotic members. This change was followed by caspase-9 and caspase-3 cleavage and activation in two cancer cell lines, RKO and AGS. The anti-proliferating effect of FTI-6D was remarkably detected in eight cancer cells with wild-type TP53 (TP53_wt), including RKO and AGS, but not in seven cancer cells with mutated TP53 (TP53_mut). Additionally, p53 protein levels increased after FTI-6D treatment in TP53_wt cancer cells, and the cytotoxic effect of FTI-6D was decreased by TP53 knockdown. Accordingly, the expression of p53 downstream genes involved in apoptotic signaling pathways, such as BBC3 and TP53INP1, and those involved in cell growth inhibition, such as CDKN1A, was upregulated in TP53_wt cancer cells. These results suggest that the anti-proliferative and apoptosis-inducing activities of FTI-6D rely on p53 and the corresponding signaling processes. This study demonstrated that FTI-6D shows anti-cancer activity against TP53_wt cancer cells. FTI-6D may have potential as a prototype compound for a new drug to utilize a functional p53 pathway in TP53_wt cancer cells.

A Pilot Study of Determining the Reliability of a New Three-Dimensional Scanning System for Measuring Truncal Thickness After Breast Cancer Surgery.

Background: Lymphedema often affects the trunk after breast cancer surgery. Measuring volume baseline can help detect lymphedema-related changes early, thereby allowing for early intervention efforts. However, there is no quantitative method for detecting truncal lymphedema. As a preliminary investigation into the development of a new method for measuring truncal lymphedema, this study aimed to investigate the reliability and define the minimal detectable change (MDC) in posterior truncal thickness using a three-dimensional (3D) scanning system. Methods and Results: This observational study included 21 women who had undergone a mastectomy for breast cancer. The 3D images of every subject's trunk were captured by a handheld 3D scanner at two time points. The acquired 3D images were used to calculate the differences in thickness between the affected and unaffected sides at eight points on the trunk. The reliability was determined by checking for agreement between the trials (intraclass correlation coefficient) and by investigating the presence of systematic bias between the measurement error and true value (Bland-Altman analysis). Then, the MDC was calculated. For 14 of the 21 participants, 3D images without missing data at both time points were obtained. Analysis indicated that there was no systematic bias regarding the mean value at the seven body points. Fair-to-excellent reliability was shown at the five points in the middle of the trunk (MDC: 4.14-9.79 mm). The other three points (at the top and bottom of the trunk) had limited reliability. Conclusions: The 3D scanning system effectively measured the differences in thickness between the affected and unaffected sides of participants' posterior trunks, with fair-to-excellent reliability in the middle of the trunk.

The Correlation Between Fluid Distribution and Swelling or Subjective Symptoms of the Trunk in Lymphedema Patients: A Preliminary Observational Study.

Background: Manual lymph drainage (MLD) is one of the common treatments for breast cancer-related lymphedema (BCRL). Although the primary goal of MLD is to drain the excessive fluid accumulated in the affected upper limb and trunk to an area of the body that drains usually, the use of MLD is decided based on swelling and subjective symptoms, without assessing whether there is fluid accumulated in the affected region. The purpose of this study was to examine truncal fluid distribution in a sample of BCRL patients and investigate any correlation between such fluid distribution and swelling or subjective symptoms. Methods and Results: An observational study was conducted with 13 women who had unilateral, upper extremity BCRL. Fluid distribution was evaluated by using two magnetic resonance imaging (MRI) sequences: half-Fourier acquisition single-shot turbo spin echo and three-dimensional double-echo steady-state. The presence of swelling was determined by lymphedema therapists, and subjective symptoms were measured by using a visual analog scale. On MRI, no participants had any free water signals in the trunk. However, seven had swelling and all 13 had some kind of subjective symptoms on the affected side of their trunk. Conclusions: These results suggest that swelling and subjective symptoms do not correlate with the presence of truncal fluid. For such cases, a different approach than MLD may be needed to address truncal swelling and related subjective symptoms. Checking for the presence of fluid in the truncal region may help MLD be used more appropriately.