Salinomycin – a breakthrough in the treatment of ovarian cancer?

Adam Huczyński1, Janina Markowska2, Rodryg Ramlau2, Stefan Sajdak3, Sebastian Szubert3, Katarzyna Stencel2 Received: 12.10.2016 Accepted: 04.11.2016 Published: 30.11.2016 © Curr Gynecol Oncol 2016, 14 (3), p. 156–161 DOI: 10.15557/CGO.2016.0018 Salinomycyna – przełom w leczeniu raka jajnika? Salinomycin – a breakthrough in the treatment of ovarian cancer?


D
espite progress in molecular biology and the identification of mechanisms associated with the growth, division, metastasis and response to chemotherapy, the 5-year survival rate in advanced ovarian cancer is only 30-50% (1) .Although 50-70% of patients achieve a complete response to treatment after cytoreduction surgery and subsequent chemotherapy, 80% of patients experience a relapse in which the disease is more aggressive and resistant to chemotherapy (2,3) .

MARKERY KOMÓREK MACIERZYSTYCH RAKA
ensures the self-renewal of CSCs, Notch affects not only the survival of CSCs, but also their interactions with other cells.Hedgehog participates in the proliferation and differentiation of CSCs (4,10,14,16) .

CANCER STEM CELL MARKERS
Cancer stem cells may be identified and isolated based on specific biomarkers.Numerous studies on cell lines and animal models have demonstrated that the most commonly detected molecular markers of ovarian CSCs include: CD44, CD133, CD117, Oct-4 (POUSF1) and nestin.CD44 is a cell surface glycoprotein.It participates in cell adhesion.CD44 binds the components of the cell matrix and through its degradation CSCs achieve a metastatic potential.The CD44 glycoprotein increases the synthesis of GSH (glutathione), due to which CSCs acquire the ability to neutralize reactive oxygen species (ROS) and present the malignant phenotype.In addition, CD44 interacts with hyaluronic acid with the use of the Nanog transcription factor; as a result, CD44 causes chemotherapy resistance in CSCs, which has been confirmed both in cell cultures and in animal models (3,8,12,(17)(18)(19)(20)(21) .CD133 is a transmembrane glycoprotein participating in drug transport.Studies on ovarian cancer tissues demonstrated a higher expression of CD133 in relapse and metastatic cancers than in primary lesions.A correlation with poor prognosis for ovarian cancer was found (3,17,22,23) .CD117 (c-Kit) is a type III tyrosine kinase receptor which is also present in embryonic cells and dormant cells.This marker is associated with ovarian cancer chemotherapy resistance (3,6,17) .BMi1, Oct-4 (POUSF1) and nestin are proteins constituting the marker picture of ovarian CSCs.BMi1 displays the activity of a proteasome.It participates in CSC renewal, similarly to Oct-4 (transcription factor) and nestin, a component of fibrous proteins of the cell cytoskeleton.All of these proteins are associated with resistance to cytostatics (12,17,24) .According to Shah and Landen (4) there has been no consensus so far regarding a universal marker or collection of markers which permit the identification of a cancer stem cell population resistant to ovarian cancer therapy; this is because these cells evade cytostatic therapy using the various methods described above.However, a growing body of evidence has been accumulated showing that CSC eradication therapy is possible.Massard et al. (10) claim that CSCs, which are the cause of treatment failure, should be either allowed to differentiate into mature forms or eliminated.The elimination of CSCs seems possible with the use of salinomycin.
albus by Miyazaki et al. (25) in 1974 in Japan during antibiotic screening studies.Salinomycin disrupts the Na + /K + ion balance in biological membranes, which leads to cell apoptosis.In 2009 Gupta et al. (26) announced that this antibiotic was nearly 100 times more effective in the eradication of breast cancer stem cells than taxol.In 2010 Naujokat et al. (27) discovered that salinomycin induced apoptosis in leukemia cells resistant to chemotherapy.Subsequently, Lu et al. (28) demonstrated that the induction of apoptosis of cancer cells in chronic lymphocytic leukemia occurred through the inhibition of the Wnt signaling pathway, which plays a role in the self-renewal of stem cells (4,10,29) .Salinomycin displays resistance to the action of the ABC transmembrane transporters due to the size of the molecule (75 kDa), thanks to which it is not pumped out of the cell.Apart from that it inhibits MDR1 (11,30,31) .It has also been reported that salinomycin causes CSCs to differentiate and may lead to their elimination through this mechanism.It has been proved that CSCs which are resistant to taxol, 5-fluorouracil and cisplatin are sensitive to salinomycin (26) .A review by Antoszczak and Huczyński (32) reports anticancer activity of salinomycin in many types of cancer -in cell lines, animal models as well as people.
A pioneer in the treatment of cancer with salinomycin is Professor Cord Naujokat from Heidelberg, who treated a 40-year-old woman with metastatic breast cancer and an 82-year-old woman with diffuse vulvar cancer and achieved a good treatment response (27) .The side effects of the therapy are small -hand tremor and transient mild tachycardia within 30-60 minutes of the administration of the drug (27) .

ACTIVITY OF SALINOMYCIN IN OVARIAN CANCER
In 2013 Parajuli et al. (33) demonstrated that salinomycin destroyed ovarian CSCs resistant to cisplatin in vitro and in vivo.The route to eliminate CSCs leads through an increase in the expression of the death receptor 5 (DR5) and caspase 8, an apoptosis execution enzyme.The same group of researchers also indicated another route of elimination of ovarian cancer stem cells resistant to cisplatin.The administration of salinomycin to in vitro and in vivo cell lines inhibited the nuclear transcription factor (NF-κB), which takes part in apoptosis (34) .Zhang et al. (35) conducted similar research on six human ovarian cancer cell lines resistant to cisplatin; they used various doses of salinomycin within 24-72 hours.The proportion of cells which underwent apoptosis depended on the dose and duration of action of salinomycin.Apoptosis was present in all the cell lines.The authors believe that the induction of apoptosis in CSCs is caused by the activation of MAPKp38, a signaling pathway for cascade-activated enzymes which take part in the differentiation and apoptosis of cells.