cancer patients. Examples of such inhibitors include anti-breakpoint cluster region­Ab1 (BCR-ABL1), anti-human epidermal growth factor 2 (HER2), and anti­epidermal growth factor receptor (EGFR) inhibitors. Additionally, there are ongoing assessments of these inhibitors in various clinical trial studies [3, 4].

comprehensively analyze the heterogeneity of tumor cells, researchers have devel­oped xenograft models involving the transplantation of human cancer cells into mice. These models have revealed that cells within numerous human cancers exhibit a hierarchical organization, wherein only a small subset possesses the capacity to initiate and sustain tumor growth over an extended period of time. These cells exhibit numerous phenotypic and functional characteristics that are typically observed in regular stem cells. They are commonly referred to as cancer stem cells (CSCs) due to their ability to self-renew indenitely and generate tumorigenic off­spring. It has been extensively shown that CSCs play a crucial role in the initiation, progression, metastasis, and resistance to therapy of tumors [10, 11]. Despite nota­ble advancements in the realm of prostate cancer therapy, there is a lack of compre­hensive understanding of the processes that contribute to chemoresistance in prostate cancer and the development of castration-resistant prostate cancer (CRPC). Therefore, the investigation of the phenotypic and genetic characteristics, as well as the molecular regulators, of prostate cancer stem cells (PCSCs) could provide valu­able knowledge regarding the identication of cells responsible for CRPC and offer an improved insight into the mechanisms that are at the foundation of chemoresis­tance in prostate cancer. This research could serve as a basis for the development of innovative therapeutic approaches that specically target PCSCs [11]. The develop­ment of chemoresistance is attributed to a combination of intricate molecular pro­cesses, such as the activation of abnormal androgen receptor and/or ATP-binding cassette (ABC) family of membrane transporters, repression of tumor-suppressor gene expression, evasion of programmed cell death, intercommunication among crucial signaling pathways, and involvement of various miRNAs [12]. This section aims to provide a comprehensive overview of the many roles played by ABC sub­family G member 2 (ABCG2), AR, important signaling pathways, PCSCs, and miRNAs in the development of chemoresistance in prostate cancer. Additionally, it will explore emerging therapy approaches, with a particular focus on medicines targeting PCSCs [12].

beginning and progression of prostate cancer. These factors underlie the success of androgen deprivation therapy (ADT) [15]. Since the rst discovery by Huggins and Hodges in 1941 that prostate cancer is sensitive to hormones and castration may serve as an effective treatment, continuous efforts have been dedicated to suppress­ing and eliminating AR signaling [16]. Regrettably, despite the considerable ef­cacy of surgical or chemical castration in reducing tumor burden, lowering serum PSA levels, and enhancing survival rates in the early stages of therapy, prostate cancer inevitably relapses within a median length of 12–24months and progresses to CRPC over time [17]. In the past, PCa that did not respond to hormonal manipu­lation was referred to by other terms such as hormone-refractory/resistant PCa (HRPC) or endocrine-resistant PCa (ERPC). However, nowadays, the term CRPC is frequently used. The conventional description of CRPC has certain characteristics, which are as follows: (1) The serum testosterone levels following castration are found to be below 1.7nM, which is signicantly lower than the normal range of 10–35nM. (2) The prostate-specic antigen (PSA) shows a pattern of three con­secutive increases, occurring at two-week intervals, resulting in two instances where the PSA level rises by 50% compared to the lowest recorded value. (3) The discon­tinuation of anti-androgen therapy for a minimum duration of four weeks. (4) Despite implementing additional hormonal interventions, there is evidence of con­tinued progression of PSA levels. (5) The presence of metastasis, indicating the spread of cancer to other parts of the body [18]. One of the primary distinguishing features of CRPC is its capacity to endure low levels of androgens. It has been shown that CRPC cells continue to depend on AR signaling, despite the fact that the circulating testosterone levels drop below 1.7nM after castration [19]. Numerous investigations have shown that cells of CRPC have mutant AR, resulting in increased gene expression and heightened functional sensitivity. In the context of clinical set­tings, it has been reported that prostate cancer cases that have had androgen depriva­tion therapy have a higher prevalence of AR amplication, promiscuity, and splice variant isoforms in comparison to cases of primary prostate cancer that have not received any treatment [20]. Hence, there is a prevailing belief that the majority of cases of CRPC are not really hormone refractory. This refers to instances when androgen receptor transcription is abnormally reactivated, despite the presence of low levels of testosterone in the bloodstream after castration [21]. Conversely, muta­tions affecting the AR sequence were identied in ~45% of instances of CRPC [22]. Thus far, a multitude of genetic alterations in the AR gene have been documented, with about 91% classied as mis-sense and non-sense mutations [23]. These muta­tions in the AR mostly manifest in the LBD and NTD, whereas a mere 7% of muta­tions are seen in the DBD and a mere 2% in the hinge region. The therapeutic signicance of genetic alteration in the LBD lies in their shown ability to enhance sensitivity and reduce selectivity in ligand binding. One notable point mutation, known as T877A, has been discovered as the most prevalent. This mutation enables the activation of the receptor by many anti-androgens, including progestin, estro­gen, and hydroxyutamide. Furthermore, there is a possibility of observing a with­drawal reaction in particular patients with the T877A mutation. This is evident when the anti-androgen bicalutamide is administered intermittently, resulting in a

decline in prostate-specic antigen levels [24]. This nding provides additional sup­port for the hypothesis that AR mutations may underlie the acquired androgen-like agonistic effects associated with continuous administration of anti-androgens, such as bicalutamide.

samples of human castration-resistant prostate cancer [33]. Collectively, the afore­mentioned studies indicate that PCSCs, or a pool of PCSCs that may consist of several subsets of cells resistant to chemotherapy, have the potential to serve as the genesis of CRPC.Furthermore, these PCSCs are likely to contribute, to some extent, to the development of chemoresistance in prostate cancer.

additional pathways. The Nrf-2 protein is responsible for activating the transcrip­tion of molecules that possess antioxidant properties, as well as molecules that inhibit programmed cell death (apoptosis). The Nrf2 pathway is used by the signal­ing molecule mTOR to enhance the expression of glutathione as a means of increas­ing resistance to radiation [47]. Besides transcription factors like HIF-1α and Nrf-2, the activation of the NF-κB pathway constitutes a noteworthy mechanism contribut­ing to radioresistance, particularly in cells of prostate cancer origin.