Frontiers in Clinical Drug Research - Anti-Cancer Agents: Volume 6

Atta-ur-Rahman

• Verlag: Bentham Science Publishers
• Jahr: 2021
• ISBN:
  9789811478437
• Thema: Scienze fisiche
• Thema: Chimica clinica

Frontiers in Clinical Drug Research - Anti-Cancer Agents is abook series intended for pharmaceutical scientists, postgraduate students andresearchers seeking updated and critical information for developing clinicaltrials and devising research plans in anti-cancer research. Reviews in eachvolume are written by experts in medical oncology and clinical trials researchand compile the latest information available on special topics of interest tooncology and pharmaceutical chemistry researchers. The sixth volume of the book features reviews on these topics: · Immunomodulating Agents in The Treatment ofAcute Myeloid Leukemia · Potential Natural Products for Prostate CancerManagement· Inhibition of Key Protein-Protein Interactions bySmall Molecules for Cancer Drug Design· Efficacy of Hepatic Arterial InfusionChemotherapy (HAIC) For Advanced Hepatocellular Carcinoma· Targeting Cancer Stem Cells: Implications inHealth and Disease

Potential Natural Products For Prostate Cancer Management: Prospects For Castration-Resistant Patients

Thaise G. Araújo^{1, *}, Lara Vecchi¹, Danilo S. Costa², Sara T. S. Mota¹, Paula M. A. P. Lima¹, Igor M. Campos², Mariana A. P. Zóia¹, Douglas C. Brandão¹, Gabriela S. Guimarães¹, Matheus A. Ribeiro¹, Ademar A. da Silva Filho²

¹ Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, Brazil

² Faculty of Pharmacy, Department of Pharmaceutical Sciences, Federal University of Juiz de Fora, Juiz de Fora, Brazil

Abstract

Prostate Cancer (PCa) is a major global health burden with alarming epidemiological indices. Research advances in this area have revealed complex molecular aspects associated with the disease, thus necessitating the novel development of diagnostic methods and therapeutic strategies. The main molecular target is the androgen receptor (AR), which is involved in both normal development and malignant transformation. However, many patients become resistant to conventional treatments, and the disease progresses to a castration-resistant stage (CRPC) in which tumor aggressiveness is driven by a constitutive activation of AR signaling. Tremendous effort has been made for elucidating CRPC and chemoresistance. In fact, multiple signaling pathways are related to the insurgence and maintenance of CRPC, highlighting the need for continuously updating such a complex scenario. Different drugs have been tested and used for CRPC treatment, facing unfavorable heterogeneity and leading to substantial morbidity and mortality. Thus, the clinical impact of advanced PCa with poorer outcomes still underscores the need for new compounds. The discovery and current use of natural products has given way to promising possibilities, offering alternative tools that aim to control the disease and to better manage patients. These natural products are versatile and effective molecules with different mechanisms of action and structures. In the present chapter, we explore the challenges of PCa and describe recent scientific contributions in this field, with special attention devoted to CRPC. We also discuss and suggest natural products as potential novel anti-tumor agents to overcome clinical limits and to treat and cure CRPC patients.

Keywords: Castration-Resistant, Chemotherapy, Phytochemicals, Prostate Cancer, Treatment.

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^* Corresponding author Thaise Gonçalves Araújo: Laboratory of Genetics and Biotechnology, Institute of Biotechnology, Federal University of Uberlandia, Rua Major Jerônimo, 566, Sala 604, 384700-128, Patos de Minas, MG, Brazil. Tel: [phone]; E-mail: [email protected]

INTRODUCTION

Prostate cancer (PCa) is a hormonally-driven tumor that ranks fourth in incidence among human cancers and caused 358, 989 deaths worldwide in 2018 [1, 2]. When PCa is localized to the prostate and surrounding tissues, the overall survival (OS) rates are significantly high since these patients are efficiently treated with surgery and radiotherapy [3]. However, over 20% of patients evolve to a lethal treatment-refractory stage of the disease with OS ranging from 26% to 30% at 5 years [4].

Advanced PCa is treated with chemotherapy and, mainly, associated with androgen deprivation therapy (ADT) [5]. In chemotherapy, cytotoxic drugs are introduced to control or cure the disease, targeting circulating tumor cells. However, it also affects normal cells, which results in undesirable side effects [6]. In some PCa patients, it is not possible to reach a complete abrogation of the androgen receptor (AR)-mediated functions through ADT. Such a scenario is due to the ability of PCa cells to elicit aberrant AR signaling that sustains tumor progression towards castration-resistant PCa (CRPC) [7].

Current chemical therapies often fail to control PCa, especially CRPC [3]. Notably, the fact that Natural Products (NPs) present fewer side effects and greater efficacy, together with their ability to act on several cellular mechanisms, makes them particularly promising in the treatment of tumors. The ability of NPs to inhibit PCa has already been described and, owing to their low toxicity, they confer clear advantages over synthetic compounds used to control CRPC [6]. Herein, we discuss general aspects of PCa, focusing on CRPC. Considering that CRPC is characterized biochemically by increasing levels of AR-targeted genes, blocking the receptor-dependent transcriptional programmers is of particular interest. Hereafter, we describe the mechanisms of action of different NPs and their potential application for the management of advanced PCa, especially for modulating AR signaling.

OVERVIEW OF PROSTATE CANCER

Epidemiology and Etiopathology

The development of the human body is a complex and highly regulated process that needs a molecular equilibrium in order to carry out its essential functions [8]. Such an equilibrium is lost in the tumorigenesis process during which normal cells progressively evolve towards a neoplastic state. There are six hallmark traits that enable cells to become malignant, including sustained proliferative signaling, growth suppression evasion, cell death resistance, replicative immortality, sustained angiogenesis, and tissue invasion and metastasis. Such characteristics are also associated with genomic instability, reprogramming of energy metabolism, inflammation processes and evasion from immune destruction, which are responsible for the promotion and progression of cancer [9^-11].

The progressive colonization of several sites of the body is the main cause of cancer-induced morbidity and relies on the capacity of cancer cells to invade tissues. During invasion, the extracellular matrix (ECM) is degraded and cancer cells survive in the lymphatic and vascular systems [12^-15]. Epithelial-mesenchymal transition (EMT) is at the center of the metastatic process since it confers to cancer cells a more aggressive potential and allows the generation and accumulation of cancer stem cells (CSCs) in a highly dynamic and heterogeneous tumor microenvironment [14, 16].

Despite the notable advances in treatment methods and in detection of malignant neoplasms, cancer remains a major public health problem. Its epidemiological indexes are alarming, including its high incidence and mortality [17, 18]. The incidence of cancer in Brazil and in the world is growing at an accelerated pace, following the aging of the population (due to the increase in life expectancy) and the change in global lifestyles [19]. In 2017, according to the World Health Organization (WHO), there were 8.8 million cancer deaths worldwide with the vast majority in developing countries. About 12 million deaths are predicted by the year 2030 [17].

PCa, in absolute global values, is the fourth most common type and has the second highest incidence among men [17]. In 2018, 1.3 million new cases of PCa were registered worldwide with 358,989 deaths. The highest incidence of the disease was in Europe (449,761 - 35.2...