Global Journal of Medical Research, F: Diseases, Volume 23 Issue 2

CSC populations are thought to drive chemoresistance and cancer relapse because of the capacity to self-renew and specialize into a variety of cancer cell lineages in response to chemotherapeutic drugs. Additionally, CSCs have the capacity enter a quiescent non-proliferative state, which supports their capacity to resist chemo- and radio-therapy[33]. Commonly used chemotherapy drugs induce apoptosis in dividing cells. Although effective cancer treatments kill most growing tumor cells, some CSCs survive because of decreased proliferation and chemoresistance and can initiate a relapse [25]. Special Emphasis: Implications of CSCs on Anti- Androgen Therapy Response Male patients with castration-resistant prostate cancer (CRPC) have the option of treatment with the androgen receptor (AR) antagonist enzalutamide [14]. However, there area significant number of patients that do not respond to the treatment, and the causes behind this resistance are mostly unknown. Research by Alumkal et al. (2020) showed that those with enzalutamide resistance should be enrolled in clinical studies to collect tissue biopsies and apply medications to overcome resistance [14]. Menssouri et al. (2021) posited that AR resistance is related to multiple transcriptional processes that were previously active in pre-treatment samples[34]. O’Reilly et al. (2019) showed that CSCs and tumor relapse are connected on many levels. Also, hypoxic conditions that result from AR resistance cause a variety of signaling pathways to be activated, which elevates stem cell markers and promotes prostate CSC proliferation[35]. Thus, targeting hypoxic signaling pathways might prevent stem cell appearance and lessen resistance. Androgen deprivation therapy resistance has been found to be facilitated by increased expression of Fra1 and PTTG1, which is induced by STAT3 binding to their promoters[21]. Similarly, the stemness of glioblastoma cells is maintained when RTVP1 expression is promoted by the binding of both C/EBP β and STAT3 to the RTVP-1 promoter, which is linked to poor clinical outcomes[21]. These findings open the door to a more thorough comprehension of the significance of CSC in castration- resistant prostate cancer and resistance to AR antagonism with enzalutamide[36]. Recently, cell plasticity has become a target for therapy in prostate cancer. Tumor cells may transform into a distinct subtypes in response to anticancer therapy, such as the neuroendocrine phenotype, which is linked to treatment failure [37]. Sánchez et al. (2020) proposed a new mechanism for the plasticity of prostate cancervia AMP protein kinase[37]. Prostate cancer cells showed signs of neuroendocrine morphology and expressed more neuroendocrine markers and neuron- specific enolase, which was correlated with increased expression of stem cell markers and resistance to AR [37]. In stem-like cells, overexpression of AMPK reduced the expression of stem markers and hypoxia-inducible factor (HIF-1). Also, docetaxel sensitivity was restored in stem-like AMPK-transfected cells [37]. IX. S temness as a T herapeutic T arget a) Sensitizing cancer stem cells to cytotoxic therapy/radiation One promising method for sensitizing breast cancer stem cells (BCSCs) to cytotoxic therapy is targeting the Fbxw7 gene, which maintains cell dormancy. Inhibition of Fbxw7 stimulates BCSCs to progress from the G0 quiescence phase can sensitize these CSCs to current therapies [38], [39]. The antirheumatic drug, sulfasalazine, has also shown to be effective in achieving therapy success by making CSCs more sensitive to radiation [38]. Targeting ATM signaling using an ATM inhibitor is able to resensitizeCD44+/CD24− BCSCs to radiation [38]. Similarly, inhibition of ATM/ATR signaling and downstream targets such as PARP1 and Wee1 increased the sensitivity of CSCs of multiple cancer types to chemotherapy and radiation [40]. Moreover, the promotion of BCSCs development by HIF-1 α in hypoxic conditions can be targeted using ganetespib (a second- generation HSP90 and HIF-1 α inhibitor)to sensitize BCSCs to chemotherapy in vivo and in vitro [38]. In addition, sequential treatment of patient-derived colorectal cancer xenografts with 5-fluorouracil (5-FU) or chemoradiotherapy (CRT) followed by evofosfamide (a hypoxia-activated prodrug) inhibited tumor growth and decreased the colorectal cancer initiating cell fraction [41]. Furthermore, Croker et al. showed that the inhibition of ALDH activity by using ALDH inhibitors, such as all-trans retinoic acid (ATRA) and diethylaminobenzaldehyde (DEAB), can make TNBC cells more sensitiveto chemotherapy and radiotherapy [42]. Similarly, silencing ALDH gene expression in ALDH-expressing ovarian CSCs reverses chemoresistance in these cells [43]. 20 Year 2023 Global Journal of Medical Research Volume XXIII Issue II Version I ( D ) F © 2023 Global Journals Cancer Stem Cells as the Key to Cancer: Special Emphasis on Prostate Cancer Another method for sensitizing CSCs is by targeting NOTCH signaling, which has been shown to sensitize patient-derived glioma stem cells to radiotherapy in vitro and to prevent xenograft formation [44]. In addition, inhibiting WNT/ β -catenin pathway by using imatinib, a c-KIT/CD117 inhibitor, or anti-CD117 siRNA can reverse chemoresistance [45]–[48]. This was shown in pre-clinical models where the number of cancer stem cells decreased in squamous cell carcinoma and breast cancer xenografts, allowing therapeutic resistance to be overcome [48]–[50][. Nanotechnology has offered a novel way to target CSCs by enhancing local drug delivery. For example, PEGylated gold nanoparticles fused with anti-CD44 antibody greatly enhanced the targeting of breast and gastric cancer stem cells [51], [52]. In addition, using