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Inactivation of nuclear factor ?B by MIP-based drug combinations augments cell death of breast cancer cells.

ABSTRACT: BackgroundDrug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects.Materials and methodsIn the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-?B) and tested in Western blot analysis. Inactivation of NF-?B was confirmed by p65 and I?B?, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression.ResultsAll combinations confirmed intrinsic apoptosis activation and NF-?B inactivation.ConclusionDouble and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.

SUBMITTER: Subramaniam M

PROVIDER: S-EPMC5935191 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells.

Subramaniam Menaga M Liew Su Ki SK In Lionel LA L Awang Khalijah K Ahmed Niyaz N Nagoor Noor Hasima NH

Drug design, development and therapy 20180501

<h4>Background</h4>Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects.<h4>Materials and methods</h4>In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), <i>Mycobacterium indicus pranii</i> (MIP) and cisplatin (CDDP) against 14 various human cancer cell ...[more]

PMID: 29750018

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Project description:Current prognostic factors are insufficient for precise risk-discrimination in breast cancer patients with low grade breast tumors, which, in disagreement with theoretical prognosis, occasionally form early lymph node metastasis. To identify markers for this group of patients, we employed iTRAQ-2DLC-MS/MS proteomics to 24 lymph node positive and 24 lymph node negative grade 1 luminal A primary breast tumors. Another group of 48 high-grade tumors (luminal B, triple negative, Her-2 subtypes) was also analyzed to investigate marker specificity for grade 1 luminal A tumors. From the total of 4405 proteins identified (FDR < 5%), the top 65 differentially expressed together with 30 previously identified and control markers were analyzed also at transcript level. Increased levels of carboxypeptidase B1 (CPB1), PDZ and LIM domain protein 2 (PDLIM2), and ring finger protein 25 (RNF25) were associated specifically with lymph node positive grade 1 tumors, whereas stathmin 1 (STMN1) and thymosin beta 10 (TMSB10) associated with aggressive tumor phenotype also in high grade tumors at both protein and transcript level. For CPB1, these differences were also observed by immunohistochemical analysis on tissue microarrays. Up-regulation of putative biomarkers in lymph node positive (versus negative) luminal A tumors was validated by gene expression analysis of an independent published data set (n = 343) for CPB1 (p = 0.00155), PDLIM2 (p = 0.02027) and RELA (p = 0.00015). Moreover, statistically significant connections with patient survival were identified in another public data set (n = 1678). Our findings indicate unique pro-metastatic mechanisms in grade 1 tumors that can include up-regulation of CPB1, activation of NF-κB pathway and changes in cell survival and cytoskeleton. These putative biomarkers have potential to identify the specific minor subpopulation of breast cancer patients with low grade tumors who are at higher than expected risk of recurrence and who would benefit from more intensive follow-up and may require more personalized therapy.

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Inactivation of nuclear factor ?B by MIP-based drug combinations augments cell death of breast cancer cells.

Publications

Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells.

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