**3.8 Metformin is a potential LC targeting agent by suppressing the AMPK pathway**

Metformin is an anti-diabetic drug reducing blood glucose and insulin levels through activation of adenosine monophosphate-activated protein kinase (AMPK) to inhibit gluconeogenesis in the liver [149]. In cancer cells, AMPK activation results in mTOR pathway inhibition and therefore inhibition of cell proliferation [150]. So far, several epidemiological studies focusing on ovarian cancer patients with type 2 diabetes who were taking metformin at the time of diagnosis showed that these patients had a significantly improved 5-year survival rate compared to those who did not take metformin [151, 152]. Currently, there are multiple clinical trials submitted in the national institute of health (NIH) clinical trial database focusing on non-diabetic ovarian cancer patients being treated with a combination of metformin and first line chemotherapy. The results from one of the completed phase II studies (NCT01579812) showed that the tumours in women treated with metformin had a significantly fewer ALDH1+ cells representing OC stem cells [153], therefore, supporting the use of this drug in the next phase of clinical trials. Furthermore, investigations in our lab evaluated the effect of sitagliptin, a drug used for the treatment of type 2 diabetes, in a murine model of ovarian cancer showing that sitagliptin enhanced the immune response via T cell recruitment to the tumour and inhibited several pro-tumorigenic cytokines, therefore reducing tumour burden and improving survival [154].

### **3.9 Non-steroidal anti-inflammatory drugs are potent cytotoxic LC inhibitors**

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac and celecoxib are mainly prescribed to reduce pain, fever and inflammation [155]. Inflammation has a key role in cancer development and progression, therefore, NSAIDs have been shown to exhibit protective roles against this disease [156]. This effect is mediated through the inhibition of cyclooxygenase-1 and 2 (COX-1,2) enzymes inhibiting prostaglandin (PG) synthesis [157]. While constitutive expression of COX-1 regulates tissue homeostasis through PG synthesis, COX-2 is not expressed in normal epithelial tissues and is only induced during inflammation.

**149**

duration of treatments.

worth further exploration.

**4. Conclusion**

*Targeting Leader Cells in Ovarian Cancer as an Effective Therapeutic Option*

In addition, this marker is found to be overexpressed in epithelial tumours [158]. COX-2 inhibition eventually leads to the induction of apoptosis and the inhibition of tumour invasion [159]. The action of NSAIDs has been further linked to PI3K signalling pathway [160, 161] and the inhibition of NFКB that leads to dysregulation of the genes involved in cancer progression and apoptosis [162]. The benefit of NSAIDs in cancer prevention and treatment remains controversial and tumour type dependant [156]. Re-assessing case–control and cohort studies from 1950 to 2011, that reported associations between aspirin uptake and cancer, showed that cancer prevention becomes significant only when the aspirin usage proceeds 5 years [162] and in this case, the overall benefit from the long-term use of NSAIDs was compromised by side-effects, such as gastrointestinal bleeding [163–165]. *In vitro* investigation of a panel of NSAIDs in ovarian cancer, showed significant apoptosis induction and reduced tumour growth in four cell lines treated with diclofenac [166]. Moreover, *in vivo* evaluation of diclofenac in mice implanted with ovarian cancer cells, showed significantly smaller tumours formed in diclofenac-treated animals compared to the control group [166, 167]. In line with this data, the drug screening platform established in our laboratory also identified diclofenac as a potent cytotoxic LC inhibitor. However, despite the growing body of evidence regarding the anti-neoplastic effects of diclofenac in OC, currently there are no clinical trials evaluating the effectiveness of this drug in patients. A phase II clinical trial to examine the effect of celecoxib treatment in combination with carboplatin in recurrent resistant ovarian cancer patients has shown promising results with a 28% RR and PFS [168], however this study did not provide any evidence of COX-2 inhibition in patients after treatment. Likewise, a phase II investigation of celecoxib plus carboplatin and docetaxel as a first-line treatment for ovarian cancer failed to demonstrate COX-2 inhibition with 82% of patients expressing COX-2 and no improvement in PFS or OS observed [169]. Furthermore, two systematic analyses on the effect of NSAID use and OC risk on big cohorts of patients failed to show such an association [170, 171]. However, both studies have indeed critical limitations with regards to the cancer subtypes, type of NSAIDs used, drug doses and the

Despite the introduction of several novel therapeutics that include targeting DNA repair pathways with Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), and vascular endothelial growth factor (VEGF) pathways with bevacizumab, the overall survival outcome for women with platinum-resistant OC remains poor. Unfortunately, women with advanced metastatic OC will eventually succumb to their disease due to the emergence of drug resistance. Understanding the mechanisms of OC migration and metastasis is crucial for the development of an effective therapeutic approach. Targeting the OC LC population serves as an attractive strategy given LCs are instrumental in orchestrating OC spread within the intra-peritoneal cavity. LCs are often highly chemo-resistant due to their stem cell-like nature and their survival post cytotoxic chemotherapy treatment may lead to therapy resistance and tumour recurrence. Multiple potential targets have been identified based on the understanding of LC biology, some of which may be targeted by re-proposing established drugs, such as dual PI3K/mTOR inhibitors, anti-helminths, statins, NSAIDs and metformin. Suppressing and eliminating LCs may be an effective therapeutic option for management of this lethal disease and is

*DOI: http://dx.doi.org/10.5772/intechopen.98689*

### *Targeting Leader Cells in Ovarian Cancer as an Effective Therapeutic Option DOI: http://dx.doi.org/10.5772/intechopen.98689*

In addition, this marker is found to be overexpressed in epithelial tumours [158]. COX-2 inhibition eventually leads to the induction of apoptosis and the inhibition of tumour invasion [159]. The action of NSAIDs has been further linked to PI3K signalling pathway [160, 161] and the inhibition of NFКB that leads to dysregulation of the genes involved in cancer progression and apoptosis [162]. The benefit of NSAIDs in cancer prevention and treatment remains controversial and tumour type dependant [156]. Re-assessing case–control and cohort studies from 1950 to 2011, that reported associations between aspirin uptake and cancer, showed that cancer prevention becomes significant only when the aspirin usage proceeds 5 years [162] and in this case, the overall benefit from the long-term use of NSAIDs was compromised by side-effects, such as gastrointestinal bleeding [163–165]. *In vitro* investigation of a panel of NSAIDs in ovarian cancer, showed significant apoptosis induction and reduced tumour growth in four cell lines treated with diclofenac [166]. Moreover, *in vivo* evaluation of diclofenac in mice implanted with ovarian cancer cells, showed significantly smaller tumours formed in diclofenac-treated animals compared to the control group [166, 167]. In line with this data, the drug screening platform established in our laboratory also identified diclofenac as a potent cytotoxic LC inhibitor. However, despite the growing body of evidence regarding the anti-neoplastic effects of diclofenac in OC, currently there are no clinical trials evaluating the effectiveness of this drug in patients. A phase II clinical trial to examine the effect of celecoxib treatment in combination with carboplatin in recurrent resistant ovarian cancer patients has shown promising results with a 28% RR and PFS [168], however this study did not provide any evidence of COX-2 inhibition in patients after treatment. Likewise, a phase II investigation of celecoxib plus carboplatin and docetaxel as a first-line treatment for ovarian cancer failed to demonstrate COX-2 inhibition with 82% of patients expressing COX-2 and no improvement in PFS or OS observed [169]. Furthermore, two systematic analyses on the effect of NSAID use and OC risk on big cohorts of patients failed to show such an association [170, 171]. However, both studies have indeed critical limitations with regards to the cancer subtypes, type of NSAIDs used, drug doses and the duration of treatments.
