Caspase-3 isoforms as variant of alternative splicing pre-mRNA caspase which acts as antagonist for Caspase-3 apoptosis executor function by inhibiting
apoptosome. Caspase-3 isoforms overexpression wil inhibit chemotherapy induced apoptosis using Etoposide and MTX. We did not evaluate the role of
Caspase-3 isoforms in our study, therefore the possibility of Caspase-3 isoforms in reducing chemotherapy induced apoptosis needs to be studied further.
An experimental study by Petanidis et al 2013 showerd the effects of cadmium Cd as carcinogen in breast cancer cultured cells line MCF-7 on cell
transformation and mestastasis. Their study result showed that Cd had a significant stimulation effect to H-Ras gene expression which will lead to
increased activity of Caspase-3 on apoptosis using 100-1000 nM Cd dose.
The role of Bcl-2, caspases family, and p53 have been established in programmed cell death, even so the role of caspase-9, -3,-7 were still discussed in
many studies. Brentnall et al 2013 studied the roles of capases-9, -3, -7 in apoptosis intrinsic process. Their results showed that three of those caspases had
different roles, Caspase-9 played a role in mitochondrial morphology changes and will be activated after cytochrome-c release and Bid into tBid in ROS forming.
While Caspase-7 was known as an effector caspase which is not involved in cell death but played a role in apoptotic cells detachment. Caspase-3 specificallya had
a role as executor after being activated by caspase-9 and another function of caspase-3 was to inhibit ROS production. A similar finding was also found in our
study.
5.4 Apoptosis Index Level Decrease Correlation with Chemotherapy Respons
Risk
Phi and Cramer’s V Test results showed that apoptosis index level decreased within 24 hours post first cycle NAC was a risk for negative
chemotherapy response in LABC patients p=0.002, therefore Apoptosis Index had a significant correlation with negative chemotherapy response in LABC.
mRNA Caspase-3 level decrease post first cycle NAC showed a linear correlation with decrease in caspase-3 or apoptosis level, this linear regression model was
found in our study.
Several study results concurred with our study on this matter. Manuaba 2006 found that apoptosis and Bcl-2 were predictive factors for chemotherapy
CAFCEF response. Millen et al 2006 studied the effects of Tamoxifen on Apoptosis Index in animal models and cultured breast cancer cells. Their
observation found that Apoptosis Index was increased within 48 hours after Tamoxifen dosing and they suggested using human subjects for future studies.
Tiezzi et al 2006 also studied the correlation between apoptosis index, p53 mutation and Bcl-2 expression post NAC in LABC. They found a correlation
between Apoptosis Index level increase with positive NAC response. Sharma et al 2008 studied changes in Bcl-2, Apoptosis Index and Caspase-3 within 24-48
hours post first cycle NAC, but they did not find any significant correlation due to small sample size. While Ali et al 2011 concluded that Apoptosis Index within
24 hours post first cycle NAC in LABC was significantly correlated with positive chemotherapy response.
Based on the resume of previous studies, results from our study were similar with similar studies. Decrease in mRNA Caspase-3 level within 24 hours
post NAC using CAFCEF had a significant correlation with negative chemotherapy response, therefore it can be used as a predictive factor for NAC
response in LABC patients. A significant correlation was also found between Apoptosis Index level decrease within 24 hours post NAC using CAFCEF with
negative chemotherapy response, therefore AI can also be used as a predictive factor for NAC response in LABC. Independently, Apoptosis Index had a stronger
correlation with chemotherapy response compared to mRNA Caspase-3. We also found a linear correlation between Apoptosis Index level decrease with mRNA
Caspase-3 level decrease, which was formulated as: Apoptosis Index Level Decrease = 38.674 + 4.109 mRNA Caspase-3 Level
5.5 Value Based Medicine
