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The Dual Topoisomerase Inhibitor P8-D6 in Breast Cancer: Comparison
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Please note this is a comparison between Version 2 by Nora Tang and Version 1 by Inken Flörkemeier.

Breast cancer constitutes the leading cause of cancer deaths among females. However, numerous shortcomings, including low bioavailability, resistance and significant side effects, are responsible for insufficient treatment. The ultimate goal, therefore, is to improve the success rates and, thus, the range available treatment options for breast cancer. Consequently, the identification, development and evaluation of potential novel drugs such as P8-D6 with seminal antitumor capacities have a high clinical need. P8-D6 effectively induces apoptosis by acting as a dual topoisomerase I/II inhibitor. 

  • breast cancer
  • drug development
  • dual topoisomerase inhibitor
  • apoptosis
  • 2D
  • 3D

1. Introduction

Breast cancer (BC) is the most lethal malignancy diagnosed in women worldwide [1], given that 13% of women will develop BC in their lifetime and 15% will die [2]. Even though BC incidence has increased in recent years, the mortality rate has decreased, mainly due to earlier diagnosis and better treatment options. The major cause of chemotherapy failure in BC treatment is chemoresistance. A variety of mechanisms to avoid the cytotoxic effects of drugs can be activated in cancer cells, e.g., decreased influx or increased efflux of drugs, activated survival pathways, or enhanced DNA repair mechanisms [3]. Thus, the development of new drugs is highly warranted.

2. The Dual Topoisomerase Inhibitor P8-D6 in Breast Cancer

The new anticancer drug P8-D6, an aza-analogous Benzo[c]phenanthridine, was synthesized with a new simple and optimized four-step approach [4]. Moreover, P8-D6 appeared as an extremely suitable anticancer drug candidate, due to its physicochemical properties and strong cytotoxic activities. Its cytotoxicity is induced by dual topoisomerase (topo) I/II inhibition. Thereby, P8-D6 functions as a topo poison and covalently stabilizes the DNA-topoisomerase complex of both topo enzymes I and II [4][5]. Human DNA topos are essential modulators of DNA topology as these enzymes regulate the untangling and unwinding of DNA strands during cellular processes such as DNA transcription, replication or recombination [6][7][8]. Due to the extension of the DNA strand breaks through the stabilization of the topo-DNA-intermediate by P8-D6, cell death is initiated by inducing apoptosis [9]. This leads to a reduction in tumor cell survival (Figure 1).
Cancers 14 00002 g001 550
Figure 1. Schematic mechanism action of P8-D6. As a topo I/II poison, P8-D6 covalently stabilizes the enzyme–DNA complex and, thus, increases the amount of single- and double-strand DNA breaks and subsequently causes cell death. The effectiveness and the broad activity spectrum of P8-D6 has been verified in in vitro studies by various labs. 
Initially, evaluation of the effectiveness of P8-D6 in cancer was tested by the National Cancer Institute, Maryland [10]. The NCI-60 DTP Human Tumor Cell Line screening resulted in an average growth inhibition of 50 % (GI50) over all 60 human tumor cell lines of 49 nM [4]. For BC cells, the result showed a GI50 value of 0.13 µM compared to cisplatin with a GI50 of 23.55 µM, etoposide with a GI50 of 1.39 µM or epirubicin with a GI50 of 0.14 µM, respectively [10]. P8-D6 also proved to be highly active in comparative studies with current standard therapeutics [11]. Cell-based two-dimensional (2D)- monolayer cell culture assays are an effective and established approach for initial drug testing [12], but three-dimensional (3D) structure models provide a more complex network of cell–matrix and cell–cell interactions, simulating the function of biological complexity more closely to in vivo settings [13][14][15]. The induction of apoptosis in BC cells was significantly higher by P8-D6 treatment compared to standard therapeutics and negative control [11]. As an example, P8-D6 increased the rate of apoptosis in MCF-7 cells by 24-fold compared to cisplatin and by 6-fold compared to topotecan. This breast cancer study clearly determined the high antitumor property of P8-D6 in molecularly different BC cell lines and ex vivo primary patient cells in 2D monolayers and 3D culture [11]. 
The development of resistances during chemotherapy contributes to therapy failure. The inhibition of both topoisomerases (topo I/II) can prevent the development of resistance, since when only one of the two enzymes is inhibited, the other is upregulated [16][17]. In addition to the high effectiveness, this is an essential advantage of dual topo inhibition. P8-D6 acts as such a dual topo I/II inhibition. Topo inhibitors play an important role in breast cancer treatment. Topo II inhibitors, such as doxorubicin, are recognized as highly active drugs for breast cancer treatment, despite their dose-dependent cardiac toxicity [17][18]. New liposomal formulations decrease the side effect profile with similar efficacy [19][20]. Topo I inhibitors are used less frequently in the treatment of metastatic breast cancer. The development of resistances during chemotherapy is the main reason for therapy failure. The inhibition of both topoisomerases (topo I/II) can prevent the development of resistance, since when only one of the two enzymes is inhibited, the other is upregulated [16][21]. In addition to the high effectiveness, this is an essential advantage of dual topo inhibition. P8-D6 acts as such a dual topo I/II inhibitor.

3. Conclusions

Breast cancer remains a challenging cancer type to treat.Continuing the development of novel drugs with higher efficacy, lower resistance potential and fewer side effects is still a clinical need in BC therapy. In order to create new therapeutic options, the targeted, cell-based preclinical testing of new active drugs is essential and forms the basis of drug development.
This present study outlines the outstanding apoptotic effect of the dual topo inhibitor P8-D6 in BC cell lines and in a translational approach in ex vivo BC primary patient cells, in both 2D monolayers and 3D culture, compared to standard therapeutics [11]. In order to prove the benefit of P8-D6 treatment for BC therapy in multiorgan systems and to verify potential toxic or side effects, further in vivo experiments would be beneficial.

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