Cisplatin in combination with zoledronic acid: a synergistic effect in triple-negative breast cancer cell lines
Authors: Toni Ibrahim
Francesco Fabbri
Laura Mercatali
Dino Amadori
Chiara Liverani
Emanuele Sacanna
Michele Zanoni
Wainer Zoli
Journal: International Journal of Oncology (2013)
Discipline: CLINICAL MEDICINE
Keywords: Zoledronic acid; bisphosphonates; antitumor activity; platinum compounds; breast cancer cell lines
Affiliations: Osteoncology Center, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), I-47014 Meldola (FC), Italy. 

Abstract:  Zoledronic acid (ZA) is the most widely used bisphos-phonate to treat cancer-induced bone disease. There is evidence that bisphosphonates have direct antitumor activity and that their combination with anticancer agents can significantly enhance the effect of treatment. We evaluated whether the combination of ZA with different platinum compounds exerts a synergistic effect in breast cancer cell lines and we investigated the mechanisms of action involved. This study was performed on four breast cancer cell lines, MCF-7, SKBR3, MDA-MB-231 and BRC-230, and confirmed on a primary culture obtained from a breast cancer bone metastasis specimen. ZA (50 µM) was administered for 72 h alone or in combination with cisplatin (Cis) or carboplatin. Drug-induced growth inhibition was detected by sulforhodamine B assay, apoptosis and cell cycle regulation were detected by flow cytometry, and protein expression was evaluated by western blot analysis. MCF-7 and SKBR3 showed very low sensitivity to the three drugs tested. The ZA + Cis combination exerted a high antitumor activity in the two triple-negative lines MDA-MB-231 and BRC-230. An important synergistic effect was obtained in MDA-MB-231 and an additive effect was observed in BRC-230. The p21, pMAPK and m-TOR pathways were regulated by this combined treatment, particularly at lower Cis doses. Carboplatin did not show antitumor activity either alone or in combination with ZA. In conclusion, the potential novel treatment schedule identified for triple-negative breast cancer could prove beneficial in view of the limited therapeutic options available for patients and also since the synergism with ZA would enable lower Cis doses to be used, thus reducing toxicity. Although further research in a clinical setting is warranted, our results on cell lines has been confirmed on a human primary bone metastasis culture. 

Retracted: No

PubPeer comments:
 2016 Corrigendum, which reads:  Following the publication of the above article, an interested reader drew an anomaly associated with the presentation of Fig. 7 to our attention. Essentially, the panel showing the Cis 0.001 data at T0 for the BRC-230 cell line was the same as that showing the Cis 0.01 data. After having re-examined our data, we realized that an error must have occurred when preparing Fig. 7. A duplication of the photo corresponding to BRC-230 Cis 0.001 T0 was incorrectly placed in the position corresponding to BRC-230 Cis 0.01 T0, while the correct BRC-230 Cis 0.01 T0 figure was erroneously positioned in the BRC-230 Cis 0.01 T1 slot. Fortunately, we had retained all of the data on our computer and were able to find the correct photos representing the conditions of BRC-230 Cis 0.01 T0 and T1. The correct version of Fig. 7 is shown below. The findings and conclusions of this paper are still supported by our experimental data and are not affected by this error. We sincerely apologize for this oversight and thank the reader for drawing this matter to our attention. We regret any inconvenience caused by our mistake. Here is the original concern about Figure 7: ![file] ,