Cancer  

Cancer, being the second leading cause of mortality globally, belongs to a highly devastating group of human diseases. It is presented with a diverse array of clinical manifestations and contributes to a significant number of deaths worldwide annually. The development of cancer involves numerous genetically distinct conditions that induce various metabolic changes within cells. Unfortunately, the wide range of mutations and metabolic pathways associated with cancer presents a significant obstacle in terms of its accurate diagnosis and effective treatment [1].

Epidemiology of Cancer

Cancer ranks as the second most prevalent cause of death on a global scale. In the year 2020, approximately 9.958 million deaths were attributed to cancer worldwide. Furthermore, there were around 19 million newly diagnosed cases of cancer in the same year. Figure 1 illustrates the number of deaths associated with each type of cancer and the distribution of the new cases across various types of cancers. Notably, lung cancer accounted for the highest mortality rate at 18% and was the second most commonly diagnosed cancer in 2020, with a prevalence of 11.7% [2] (Figure 1).

Figure 1: a) Number of Cancer Deaths in 2020, Both Sexes, All Ages. b) Number of Cancer New Cases in 2020, Both Sexes, All Ages. “International Agency for Research on Cancer

Process of Cancerogenesis

Human cancers are the made of complex, multistep processes. Some of these processes are commonly referred to as the "hallmarks of cancer" because they are widely observed across different types of human cancers. These hallmarks represent a group of functional capabilities that human cells acquire as they transition from normalcy to neoplastic abnormal cell growth states. These capabilities are crucial for the cells' ability to form malignant tumors [3].

The eight hallmarks currently comprise (Figure 2):

Figure 2: The Hallmarks of Cancer Presently Encompass Eight Basic Capabilities that are Characteristic of Cancer, as well as Two Enabling Characteristics

• Capability for sustaining proliferative signaling

• Ability to escape from growth inhibitors

• Evading cellular death

• Enabling replicative immortality

• Inducing vasculature

• Invading other tissues and organs (metastasis)

• Changing cellular metabolism pathways

• Avoiding immune system

The concept of "enabling characteristics" was introduced to address the limitations of the hallmark traits in understanding cancer pathogenesis. While the hallmark traits describe the functional capabilities of cancer cells and tumors, the enabling characteristics focus on the molecular and cellular mechanisms that allow these traits to be acquired.

In other words, the enabling characteristics are the consequences of the abnormal condition of neoplasia, which provide the means for cancer cells to develop and adopt the functional traits described by the hallmark traits. These enabling characteristics reflect the specific molecular and cellular mechanisms that allow evolving pre-neoplastic cells to acquire the aberrant phenotypic capabilities.

By studying the enabling characteristics, researchers can gain a deeper understanding of the complex molecular and cellular processes underlying the acquisition of these hallmark traits. This knowledge can ultimately lead to the development of more targeted and effective strategies for cancer prevention, diagnosis and treatment.

These processes were “genome instability” and “tumor-promoting inflammation” [3].

Occurrence

Cancer arises from a series of genetic mutations that changes cell functions. These mutations can be caused by exposure to chemical substances. For example, smoking contains various carcinogenic compounds that are known to cause lung cancer [4]. 

Furthermore, environmental chemical compounds with carcinogenic properties can lead to genetic aberrations and gene mutations [5] .

Other factors contributing to the development of cancer include bacteria, viruses and radiation. Generally, cancer disrupts the relationships between cells and results in the malfunctioning of crucial genes. This disruption can lead to disturbances in the cell cycle and abnormal cell growth [6].

Molecular Basis of Cancer

As mentioned, cancer is a multi-step process and there are several mechanisms that contribute to the development of tumours and genetic diseases encompass various mechanisms, such as:

• Chromosomal translocation, as seen in chronic blood cancer where the Bcr gene and the oncogene Abl are involved

• Point mutation, as observed in colon cancer with the Ras gene

• Deletion, as observed in breast cancer with the Erb-B gene

• Amplification, as seen in neuroblastoma with the N-myc gene

• Insertion activation, as observed in acute blood cancer with the C-myc gene

p53 gene has a complex relationship with cancerogenesis and it has been observed that p53 abnormalities are present in 60% of cases. In normal circumstances, p53 plays a crucial role in various cellular processes such as cell division, cell death, senescence, angiogenesis, differentiation and DNA metabolism. Mutations in the p53 gene impair the ability of p53 to regulate gene replication. The collaboration between p53 and CDK1-P2 and CDC2 is responsible for keeping cancer cells in the G1 and G2 phases of the cell cycle [7]. 

This occurrence results in the association of p53 with CDK2, leading to the suppression of p21's impact on the subsequent stage of the cell cycle. The anticancer function of p53 is operational through three pathways: promoting DNA repair proteins, inducing apoptosis and halting the cell cycle in the G1/S phase [8,9].

Signalling Pathways in Cancer

The abnormal signaling pathways allow cancer cells to multiply, survive and invade other tissues. Most research focus on two pathways, Ras-ERK and PI3K-Akt, which play crucial roles in multiple processes associated with cancer (Figure 3).

Figure 3: Cancer Progression

Dysregulated Signalling Pathways in Cancer

In the context of cancer, dysregulated signaling pathways can be attributed to genetic mutations. These mutations can lead to the overexpression of affected genes or the production of mutated proteins Examples of such proteins include:

• Epidermal growth factor (EGFR) that is am member of receptor tyrosine kinases (RTKs)

• Small GTPases” such as “Ras” protein

• Serine/threonine kinases” (e.g., Raf and Akt)

Ras-ERK and PI3K-Akt Oncogenic Pathways

Many cancerous genes encode components of those two pathways (Figure 4). 

Figure 4: The Ras-ERK and PI3K Pathways

Normally, these pathways are just transiently activated. Most abundant mutations are listed in Table 1.

Table 1: Mutated Proteins in PI3K-Akt Oncogenic Pathway

*PLP3: phosphatidylinositol 3,4,5-Triphosphate

Downstream mutations in tumor suppressors TSC1 and TSC2 lead to hyperactivation of mTORC1. Mutations of the Ras-ERK pathway are shown in Table 2.

Table 2: Mutated Proteins in Ras-ERK Pathway

Those two oncogenic pathways cause Recptors such as Tyrosine Kinases (RTKs) to be amplified or uncontrolled. Main members of RTKs family are EGFR, ErbB2, Fibroblast Growth Factor Receptor (FGFR) and Platelet-Derived Growth Factor Receptor (PDGFR) [10].

Angiogenesis

Tumors need a nutritional supply through blood. This can be achieved by creating new blood vessels throughout stimulating the growth and organization of endothelial cells, a process known as angiogenesis. This involves hijacking pathways typically involved in wound healing. The PI3K-Akt pathway plays a crucial role in regulating the initiation of angiogenesis and maintaining the integrity of blood vessels.

The PI3K-Akt signaling pathway is responsible for increasing HIF1 levels _a protein that triggers the production and release of VEGF by tumour cells and plays a crucial role in angiogenesis_. The activity of HIF1 is regulated by the Von Hippel-Lindau (VHL) protein, which promotes its degradation under normal oxygen conditions. VHL acts as a tumor suppressor and is often inactivated in various cancers due to mutations. Additionally, PI3K-Akt pathway produces nitric oxide and “angiopoietins” that are involved in angiogenesis [10].

Second Signal Activation & Checkpoint Pathways

These pathways involve interactions between the cellular immunity (T lymphocytes) and The Antigen Presenting Cell (APC) through second signal ligands. Initially, these pathways activate the immune response.

Pardoll has extensively studied the various second signal ligands and categorized them as either activating or inhibitory. Monoclonal antibodies known as 'checkpoint inhibitors' such as “anti-CTLA4, anti-PD-1 and anti-PDL-1” have the specificity to bind and inhibit the T-cell response mediated by CTLA4, PD-1 and PDL-1, respectively. These checkpoint inhibitors can amplify and extend tumor-specific immune responses. T cells that are targeted by these antibodies can persist in active form without being 'checked' or turned off [10].

Treatment of Cancer

Cancer Chemotherapy: Cancer chemotherapy induces a lethal cytotoxic event or apoptosis in tumour cells, leading to the arrest of cancer growth. Chemotherapy drugs are designed to target DNA or specific metabolic sites necessary for cell replication, such as purine and pyrimidine availability. However, it is unfortunate that most conventional anticancer drugs do not specifically discriminate neoplastic cells and instead affect all types of proliferating cells, both normal and abnormal.

As a result, the dose-response curve for therapeutic and toxic effects of almost all antitumor agents is steep. To address this limitation, new agents are being developed that employ a different approach to cancer treatment by blocking checkpoints and enabling the patient's own immune system to attack cancer cells. While this strategy shows significant promise, there is also concern regarding adverse effects, particularly autoimmune toxicity, in contrast to the myelosuppressive effects observed with traditional chemotherapy agents [11] (Figure 5).

Figure 5: Chemotherapy Drugs

Radiotherapy & Surgery

Radiotherapy and surgery have essential parts in the management of cancer, offering curative or palliative options depending on the stage and type of cancer. Radiotherapy utilizes high-energy radiation to target and destroy cancer cells, effectively reducing tumor burden and preventing local recurrence. It can be administered externally (external beam radiotherapy) or internally (brachytherapy), depending on the tumor location and characteristics. For instance, in breast cancer, radiotherapy following breast-conserving surgery has been shown to significantly reduce the risk of local recurrence and improve overall survival [12]. 

Similarly, in prostate cancer, external beam radiotherapy or brachytherapy can be used as primary treatment options, achieving comparable outcomes to radical prostatectomy [13]. 

Surgery, on the other hand, involves the physical removal of the tumor and surrounding tissues. It is often the preferred approach for solid tumors that are localized and amenable to resection. For example, surgical resection is the mainstay of treatment for early-stage non-small cell lung cancer, providing the best chance of cure and long-term survival [14]. In some cases, a multimodal approach combining surgery and radiotherapy may be employed to maximize treatment efficacy, such as in locally advanced rectal cancer where neoadjuvant radiotherapy is used to downsize the tumor prior to surgical resection [15]. The integration of radiotherapy and surgery in cancer treatment strategies offers a comprehensive approach to effectively control and manage the disease, leading to improved patient outcomes.

Targeted Therapy

Targeted therapies focus on inhibiting specific molecular targets in cancer cells that affect tumor growth and survival. For example, Tyrosine Kinase Inhibitors (TKIs) have shown impressive effectiveness in treating different types of cancer by blocking signaling pathways like the Epidermal Growth Factor Receptor (EGFR) pathway in non-small cell lung cancer [16].

On the other hand, immunotherapies can aid the immune system to target and eliminate tumour cells. Immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, have demonstrated remarkable clinical success in various malignancies like melanoma and lung cancer [17].

Additionally, Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a promising approach where genetically modified T cells expressing CARs specific to tumor antigens are infused into patients, resulting in long-lasting remissions in blood cancers [18].

These advancements in targeted therapies and immunotherapies have brought about a revolution in cancer treatment, providing new opportunities for improved outcomes in patients.

Thiosemicarbazones

Thiosemicarbazones (TSCs) are a type of Schiff bases which are commonly synthesized by condensing thiosemicarbazide with an aldehyde or ketone. They possess a structure of R1R2CNNHCSNR3R4, wherein R1, R2, R3 and R4 can be aromatic or heterocyclic compounds (Figure 6).

Figure 6: Synthesis of Thiosemicarbazone

The wide range of pharmacological effects exhibited by TSCs, including antiviral, antibacterial, antitubercular, antiprotozoal, antimalarial, antifungal, enzyme inhibitory and notably, antitumor properties, have made them a subject of interest for researchers in the fields of chemistry and biology [19].

Mechanism of Anti-Tumour Activity of Thiosemicarbazones

Many of TSCs have shown ability to chelate transition metals [20], Consequently, they have emerged as promising therapeutic agents with significant and selective activity [21].

In fact, TSCs could deprive tumour cells of the essential iron (Fe), which plays a crucial role in cellular metabolism and growth [22].

Several mechanisms have been suggested to explain the anti-tumour activity of TSCs, including:

• Inhibiting the uptake of iron from transferrin

• Mobilizing Fe from the cells

• Inhibiting the activity of “Ribonucleotide Reductase” (RR)

• Forming complexes which could generate “Reactive Oxygen Species” (ROS)

• Up-regulating N-myc (metastasis suppressor protein)

• Inhibiting topoisomerase

• Inducing apoptosis

Inhibiting the Uptake of Iron from Transferrin

The iron acquired by cells enters the cytosolic "Labile Iron Pool" (LIP), which is utilized by various iron-containing proteins in different cellular compartments [23]. 

Cancer cells need Fe more than normal cells. TSCs chelate iron from LIP and empties transferrin stores of Fe.

Mobilization of Iron from Cells

Increasing iron availability to tumor cells promotes cell growth, but iron chelators can deplete cellular iron, affecting targets crucial for cell proliferation, survival and metastasis [24].

Studies of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) suggest that the anti-tumor effects of the compounds are mainly due to the intracellular chelation of Fe(II) [25].

Inhibiting Ribonucleotide Reductase Activity

Inhibition of ribonucleotide reductase (RR) activity is a common mechanism of action for many anticancer drugs. The α-(N)-HCTs are proposed to be N, N, S tridentate ligands and modifying the aromatic system enhances their activity. An addendal ligand blocking model (Figure 7), has been proposed for the inhibition of enzyme activity.

Figure 7: Addendal Ligand Blocking Model

RR is an iron-dependent enzyme involved in the synthesis of deoxyribonucleotides necessary for DNA replication [26].

Generating Cytotoxic ROS

Iron has the ability to produce cytotoxic Reactive Oxygen Species (ROS), which include superoxide anion (O2• –), Hydrogen Peroxide (H2O2) and the hydroxyl radical (OH•) [27].

When Fe(II) reacts with H2O2, it generates the highly reactive OH•, which can damage biological molecules such as nucleic acids, lipid membranes and proteins. The Fe(III) produced can then be reduced back to Fe(II) by the superoxide radical O2• −.

O2• – + Fe(III) ⎯→ O2 + Fe(II)

Changes in the regulatory pathways that control Fe and ROS can cause uncontrollable proliferation of tumor cells and leads to disease progression. Several TSCs chelators with potent anti-proliferative activity have been identified, these chelators can bind to intracellular iron and copper [28]. The interaction between iron complexes and cellular oxidants and reductants leads to the generation of cytotoxic ROS [29], such as the hydroxyl radical, which can cause DNA oxidation and mitochondrial damage, resulting in cell death [27].

N-myc Gene

One promising target for cancer therapy is the Metastasis suppressor protein Ndrg-1, which plays a crucial role in reducing metastases and inhibiting angiogenesis [30]. 

Ndrg-1 is therefore a promising therapeutic target for cancer [31]. 

Iron chelators can increase Ndrg-1 expression through the transcription factor hypoxia-inducible factor-1α (HIF-1α) [32], which is upregulated under hypoxic conditions [33].

Topoisomerase Inhibition

Topoisomerases are essential enzymes for cell growth and division. [34].

There are two main types of topoisomerases in all cells: Type I (Topo I), which create single-strand breaks in DNA independently of ATP and Type II (Topo II), which create double-strand breaks in DNA [35]. 

Several TSCs have been shown to inhibit or poison topo I, topo IIα, or topo IIβ [36].

Induction of Apoptosis

Chelators can induce cancer cell aoptosis [37]. Anticancer drugs trigger apoptosis through either the death receptor (extrinsic) pathway or the mitochondrial (intrinsic) pathway [38], both of which are regulated by the p53 regulating protein [39].

Activation of the two pathways leads to the activation of enzymes called “caspases”, a group of proteases involved in apoptosis [40]. 

Initiator caspases, such as caspase-8 (in the death receptor pathway) and caspase-9 (in the mitochondrial pathway), initiate the activation of effector caspases, which cleave cellular substrates and promote apoptotic cell death [41].

In the death receptor pathway, activated death receptors recruit and activate caspase-8, which then activates effector caspases, including caspase-3. In the mitochondrial pathway, the release of holocytochrome c into the cytosol triggers the formation of an apoptosome containing holocytochrome c, Apaf-1 and procaspase-9. Activation of procaspase-9 within leads to the activation of effector caspases, which initiate terminal events similar to those induced by the death receptor pathway [41].

The major modulators of apoptosis by mitochondrial pathway are the Bcl-2 (B-cell lymphoma 2)/Bax (bcl-2- like protein 4) gene family as major modulators [37]. 

Quinoline-2-carboxaldehyde Thiosemicarbazone (QT) derivatives (Figure 8) and their Cu (II) complexes induce apoptosis in human prostate cancer cell lines by inhibiting the proteasome-ubiquitin pathway rather than through oxidative stress [42].

Figure 8: Anti-Tumour Drugs Containing a Quinoline Scaffold

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