The effectiveness of nano chemotherapeutic particles combined with mifepristone depends on the PR isoform ratio in preclinical models of breast cancer
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Gonzalo Sequeira1,*, Silvia I Vanzulli2,*, Paola Rojas1, Caroline Lamb1, Lucas Colombo3, María May1, Alfredo Molinolo4 and Claudia Lanari1
1 Institute of Experimental Biology and Medicine, IBYME-CONICET, Buenos Aires, Argentina.
2 National Academy of Medicine, Buenos Aires, Argentina.
3 Instituto Roffo, Buenos Aires, Argentina.
4 Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, USA.
* Both authors had equal participation
Claudia Lanari, email:
Keywords: breast cancer, PR isoforms, doxorubicin, paclitaxel, mifepristone, mammary carcinomas, Nab-paclitaxel, pegylated doxorubicin liposomes.
Received: February 27, 2014 Accepted: April 25, 2014 Published: April 27, 2014
There is clinical and experimental evidence suggesting that antiprogestins might be used for the treatment of selected breast cancer patients. Our aim was to evaluate the effect of albumin-bound paclitaxel (Nab-paclitaxel) and pegylated doxorubicin liposomes (PEG-LD) in combination with mifepristone (MFP) in experimental breast cancer models expressing different ratios of progesterone receptor (PR) isoforms A and B. We used two antiprogestin-responsive (PRA>PRB) and two resistant (PRA<PRB) murine mammary carcinomas growing in BALB/c, GFP-BALB/c or nude mice, along with human T47D-YA and T47D-YB xenografts growing in immunocompromised NSG mice. MFP improved the therapeutic effects of suboptimal doses of Nab-paclitaxel or PEG-LD in murine and human carcinomas with higher levels of PRA than PRB. MFP induced tissue remodeling in PRA-overexpressing tumors, increasing the stromal/tumor cell ratio and the number of functional vessels. Accordingly, an increase in nanoparticles and drug accumulation was observed in stromal and tumor cells in MFP-treated tumors. We conclude that MFP induces an increase in vessels during tissue remodeling, favoring the selective accumulation of nanoparticles inside the tumors. We propose that antiprogestins have the potential to enhance the efficacy of chemotherapy in breast tumors with a high PRA/PRB ratio.
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