Publication: INDUCTION OF INTRACELLULAR DEATH OF BREAST CANCER CELLS THROUGH COMBINED INTRACELLULAR DELIVERY OF A TUMOR-SUPPRESSOR GENE AND SMALL INTERFERING RNAS AGAINST GROWTH FACTOR RECEPTOR AND ANTI-APOPTOTIC GENES
Date
2015
Authors
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Publisher
International Medical University
Abstract
Breast cancer is one of the most common malignancies in women. It continues to be a
major burden and cause of death among women worldwide. Current treatment
strategies for metastatic breast cancer (MBC) depend upon patient and tumor
classification; menopausal status, hormone receptor status, and HER-2 status, together
with the site of metastatic disease (bone or soft tissue). The choice of treatment in
metastatic disease usually involves systemic endocrine therapy or cytotoxic
chemotherapy, with an anti–HER-2 agent when appropriate. Novel agents are
necessary in this field because many of the current therapies used in breast cancer
therapy have limitations. These include drug resistance, lack of target receptor
expression in tumors (e.g., only 25% of breast cancer tumors have HER-2
expression), lack of specificity and relatively small improvements in survival etc.
Advances in the understanding of the etiology and biology of breast cancer have
identified key targets among the multiple signaling pathways involved in the
development, growth, and survival of breast cancer cells. As such, targeted therapies
are among the most promising new agents for the treatment of breast cancer. One of
the promising approaches in this field is tumor-directed delivery of genes and gene silencing nucleic acid sequences to inhibit cancer cell proliferation and to induce
apoptosis. Both genetic and chemical engineering approaches enabled production of a
lot of vital and non-viral carriers for targeted delivery. However, considering the issue
of human safety, viral vectors are not suitable candidates for clinical uses although
they are very efficient for intracellular delivery of genes and gene silencing elements.
We have successfully developed an efficient non-viral vector system carbonate apatite
nanoparticle which is more superior to contemporary vectors used, especially for
transfecting at lower concentrations of siRNA. By employing carbonate apatite
nanoparticles, we proved that co- delivery of siRNAs, p53 gene and anti-cancer drugs
managed to block the signalling pathways. Simultaneous delivery of siRNAs-EGFR,
IGFR, ERBB2, BCL2 and p53 gene together with anticancer drugs- Cisplatin,
Doxorubicin and Paclitaxel by carbonate apatite exhibited better effects in invitro and
invivo studies in comparison with the anticancer alone treated groups where the cell
viability and tumor growth was significantly reduced to show more sensitivity
towards the drug. In conclusion the study proved that efficient delivery of p53 gene
together with the siRNAs against the growth factor receptor genes and anti-apoptotic
gene using carbonate apatite nanoparticle would effectively kill the breast cancer cells
and the synergistic effect produced by p53 gene together with siRNAs against the
growth factor receptor genes and anti-apoptotic gene and various anti-cancer drugs
provided a new insight in the treatment protocol of breast cancer. The successful
therapeutic combinations identified through the study will significantly accelerate the
identification and validation of targets for breast cancer therapy.
Description
Keywords
Breast Neoplasms, Genes, Tumor Suppressor, RNA, Small Interfering, Genes, p53, Drug Resistance