Therapeutic Inducers of Apoptosis in Ovarian Cancer.

Ovarian cancers remain one of the most common causes of gynecologic cancer-related death in women worldwide. The standard treatment comprises platinum-based chemotherapy, and most tumors develop resistance to therapeutic drugs. One mechanism of developing drug resistance is alterations of molecules involved in apoptosis, ultimately assisting in the cells' capability to evade death. Thus, there is a need to focus on identifying potential drugs that restore apoptosis in cancer cells. Here, we discuss the major inducers of apoptosis mediated through various mechanisms and their usefulness as potential future treatment options for ovarian cancer. Broadly, they can target the apoptotic pathways directly or affect apoptosis indirectly through major cancer-pathways in cells. The direct apoptotic targets include the Bcl-2 family of proteins and the inhibitor of apoptotic proteins (IAPs). However, indirect targets include processes related to homologous recombination DNA repair, micro-RNA, and p53 mutation. Besides, apoptosis inducers may also disturb major pathways converging into apoptotic signals including janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), wingless-related integration site (Wnt)/ß-Catenin, mesenchymal-epithelial transition factor (MET)/hepatocyte growth factor (HGF), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homologue (AKT)/mammalian target of rapamycin (mTOR) pathways. Several drugs in our review are undergoing clinical trials, for example, birinapant, DEBIO-1143, Alisertib, and other small molecules are in preclinical investigations showing promising results in combination with chemotherapy. Molecules that exhibit better efficacy in the treatment of chemo-resistant cancer cells are of interest but require more extensive preclinical and clinical evaluation.

Ovarian cancer stem cells and their role in drug resistance.

Ovarian cancer is typically diagnosed at advanced stages (III or IV), with metastasis ensuing at stage III. Complete remission is infrequent and is not achieved in almost half of the women diagnosed with ovarian cancer. Consequently, management and treatment of this disease is challenging as many patients are faced with tumour recurrence disseminating to surrounding organs further complicated with acquired chemo-resistance. The cancer stem cell theory proposes the idea that a drug resistant subset of tumour cells drive tumour progression, metastasis and ultimately, recurrent disease. In the ovarian cancer field, cancer stem cells remain elusive with significant gaps in our knowledge. The characteristics and specific role of ovarian cancer stem cells in recurrence still requires further research since different studies often arrive at contradictory conclusions. Here we present a review and critical analysis of current research conducted in the field of ovarian cancer stem cells and their potential role in drug resistance including several signalling pathways within these cells that affect the viability of targeted therapies.