Abstract
Simple SummaryDespite significant advancement in therapeutic strategies, breast cancers remain the most prevalent type of cancer in terms of incidence and mortality worldwide. Therefore, new alternative therapies have become an urgent clinical need. The present study shows a significantly enhanced cytotoxicity and apoptosis of a treatment with the dual topoisomerase inhibitor P8-D6 compared to standard cytostatics. These effects were visible in various breast cancer cell lines and primary patient cells in 2D monolayer and 3D spheroids. In summary, P8-D6 seems to be a potent chemotherapeutic agent for various breast cancer cell treatments.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. This study provides an overview of the effectiveness of P8-D6 in breast cancer with both 2D monolayers and 3D spheroids compared to standard therapeutic agents. For this drug effectiveness review, cell lines and ex vivo primary cells were used and cytotoxicity, apoptosis rates and membrane integrity were examined. This study provides evidence for a significant P8-D6-induced increase in apoptosis and cytotoxicity in breast cancer cells compared to the efficacy of standard therapeutic drugs. To sum up, P8-D6 is a fast and powerful inductor of apoptosis and might become a new and suitable therapeutic option for breast cancer in the future.
Highlights
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]
A major requirement for drug effectiveness is that the drug reaches its nuclear target structure-DNA-topo I and II
In addition to previous studies on colon cancer and ovarian cancer cells [5,19], this study confirms the localization of P8-D6 in the cytoplasm and the nucleus of BC cells after treatment (Figure 2A–C)
Summary
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. 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]. The new anticancer drug P8-D6, an aza-analogous Benzo[c]phenanthridine, was synthesized with a new simple and optimized four-step approach [4]. P8-D6 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 mecha of 13 nisms [3]. The development of new drugs is highly warranted
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