INTRODUCTION
CANCER
Cancer is defined as the uncontrolled growth of abnormal cells anywhere in the body. It is
accepted that cancer can develop when normal mechanism of body stops working. Old cells
do not die and instead grow out of control, forming new abnormal cells. These extra cells
may form a mass of tissue, called tumor [1]. There are different types of cancers; all types of
cancer cells continue to grow, divide and redivide instead of dying and form new abnormal
cells. Some types of cancer cells often travel to other parts of the body through blood
circulation or lymph vessels (metastasis), where they begin to grow [2].
This uncontrollable cell growth not only accumulates to form solid tumours but leads to
subsequent invasion to adjacent and distal tissues (and organs), a phenomenon which is
known as cancer metastasis. Metastasis is the leading cause of cancer morbidity and mortality
and responsible for 90% of cancer-related deaths [3]. All types of cancers have been reported
in Indian population including the cancers of skin, lungs, breast, rectum, stomach, prostate,
liver, cervix, esophagus, bladder, blood, mouth etc. The causes of such high incidence rates of
these cancers may be both internal (genetic, mutations, hormonal, poor immune conditions)
and external or environmental factors (food habits, industrialization, over growth of
population, social etc.) [4].
Cancer mortality in India has doubled from 1990 to 2016. India’s cancer incidence is
estimated at 1.15 million new patients in 2018 and is predicted to almost double as a result of
demographic changes alone by 2040 [5].
MAJOR TYPES OF CANCER:
Breast Cancer
One of the most common cancers affecting women worldwide, characterized by abnormal
cell growth in breast tissue. It can present as lumps, skin changes, or nipple discharge. Early
detection through mammography significantly improves survival rates [6].
Lung Cancer
Divided into two main types: small cell and non-small cell lung cancer. Often associated with
smoking, but can also occur in non-smokers. Symptoms include persistent cough, chest pain,
and shortness of breath [7].
Colorectal Cancer
Begins as polyps in the colon or rectum that become cancerous over time. Regular screening
after age 45 is recommended. Common symptoms include changes in bowel habits, rectal
bleeding, and unexplained weight loss [8].
Prostate Cancer
The most common cancer in men, developing in the prostate gland. Often slow-growing, but
can be aggressive in some cases. Early stages may be asymptomatic, making regular
screening crucial [9].
Melanoma
The most dangerous form of skin cancer, developing from melanocytes. Associated with UV
exposure and genetic factors. Characterized by changes in existing moles or development of
new pigmented lesions [10].
Leukaemia
A cancer of blood-forming tissues, usually the bone marrow. Produces abnormal white blood
cells that interfere with normal blood cell production. Symptoms include fatigue, frequent
infections, and easy bruising [11].
Pancreatic Cancer
Often diagnosed at advanced stages due to vague early symptoms. Affects the pancreas,
interfering with digestive enzyme production and blood sugar regulation. Poor prognosis due
to late detection [12].
Ovarian Cancer
Often called the "silent killer" due to subtle early symptoms. Affects the ovaries and can
spread throughout the pelvis and abdomen. Symptoms include bloating, pelvic pain, and
changes in urinary patterns [13].
INTRODUCTION TO PROSTATE CANCER
Prostate cancer is a malignant neoplasm that develops in the prostate gland, an essential
component of the male reproductive system. It represents the second most frequently
diagnosed cancer in men worldwide and remains a leading cause of cancer-related mortality
among males [14].
It is primarily a disease of the elderly with more than three quarter of the cases occurring in
men above 65 years of age. It is disheartening to note that approximately 4.04 million years
of healthy life are lost globally due to prostate cancer alone [15].
Smoking, obesity, race/ethnicity, diet, age, chemicals and radiation exposure, sexually
transmitted diseases, etc. are among the most common risk factors for PCa. However, the
basic change at the molecular level is the manifested confirmation of PCa [16].
Clinical presentations include: frequent urination, nocturia, haematuria, dysuria, and urinary
dysfunction. Advanced prostate cancer can spread to other parts of the body e.g., bone spine,
pelvis, and ribs, causing leg weakness and urinary and fecal incontinence. Prostate cancer is
diagnosed by biopsy, and medical imaging is done to determine if the cancer has spread to
other parts of the body. Prostate cancer screening is controversial. Prostate specific antigen
(PSA) testing increases cancer detection but does not decrease mortality [17].
According to the World Cancer Survey Statistics (GLOBOCAN), the number of newly
diagnosed cases of PCa was ~1.41 million in 2020, with ~375 thousand new deaths. By 2040,
the global PCa burden is expected to increase to 2.43 million new cases and 740 thousand
new deaths due to population growth and ageing. On the other hand, PCa incidence has been
steadily increasing in India. According to India’s population-based cancer registries, PCa is
the second most common cause of cancer in men living in metropolitan areas [18].
INCIDENCE
Prostate cancer represents one of the most significant public health challenges in male
oncology worldwide. According to recent global statistics, it ranks as the second most
frequently diagnosed cancer in men, with approximately 1.4 million new cases diagnosed in
2020, accounting for 7.3% of all male cancer cases [19]. The global distribution of prostate
cancer demonstrates striking geographical variations, reflecting complex interactions between
genetic factors, environmental influences, healthcare access, and screening practices [20].
In contrast, Asian populations historically demonstrate lower incidence rates, although
urbanization and adoption of Western lifestyles have led to increasing trends, particularly in
developed Asian nations [21].
Age plays a crucial role in prostate cancer incidence, with the disease being predominantly
diagnosed in older men. The median age at diagnosis is 66 years, with cases rarely occurring
before age 40. A sharp increase in incidence is observed after age 50, with peak rates
occurring in the 65-74 age group. The age-specific incidence rates show a dramatic
progression: 9.2 per 100,000 in men aged 40-49, rising to 312.4 per 100,000 in those over 70
years [22].
The temporal evolution of prostate cancer incidence reveals distinct patterns corresponding to
changes in screening practices. The pre-PSA era (before 1990) was characterized by lower
reported incidence and later-stage diagnoses. The introduction of PSA screening in the 1990s
led to a sharp increase in incidence rates and a shift toward earlier-stage disease detection
[23]. Contemporary trends show stabilizing or declining rates in some developed regions,
while developing nations continue to experience increasing incidence [24].
Socioeconomic factors significantly influence prostate cancer incidence patterns. Higher
reported incidence rates correlate strongly with healthcare system development and screening
availability. Urban-rural disparities in detection rates persist, even in developed nations,
highlighting the impact of healthcare access on disease identification [25]. Economic status
plays a crucial role, with high-income countries reporting significantly higher incidence rates
compared to low-income regions, although this may partly reflect underreporting and limited
diagnostic capabilities in resource-constrained settings [26].
Prostate cancer is associated with a large dispersion in incidence and death in Asian countries.
More than 60% of the world’s population lives in Asia, and most countries in the region are
developing. The cancer in the continent is expected to dramatically increase. A total of
191,054 prostate cancer cases were recorded in Asian countries in 2012. The five countries
with the highest number of patients were Japan (55,970 cases), China (46,745 cases), India
(19,095 cases), Indonesia (13,663 cases), and Turkey (12,650 cases), respectively. The five
countries include a total of 148,123 cases, 77.52 percentage of all cases in Asia [27].
PATHOPHYSIOLOGY OF PROSTATE CANCER
Prostate cancer pathophysiology follows a complex multistep process involving various
molecular pathways and genetic alterations. The disease typically begins with normal prostate
epithelial cells undergoing transformation due to both genetic and environmental factors.
Initially, these changes lead to the development of Prostatic Intraepithelial Neoplasia (PIN),
which is considered a precursor lesion to prostate cancer [28]. During this stage, significant
molecular alterations occur, particularly the TMPRSS2-ERG gene fusion, which is present in
approximately 50% of prostate cancer cases and serves as an important early event in
carcinogenesis [29].
The progression from PIN to localized prostate cancer involves several key molecular
pathways. The androgen receptor (AR) signaling pathway plays a central role, with AR
amplification and mutations becoming increasingly prevalent as the disease advances [30].
This pathway interacts closely with the PI3K/AKT/mTOR pathway, which becomes activated
through the loss of the tumor suppressor PTEN in approximately 40% of primary prostate
tumors [31]. The loss of PTEN leads to increased cell survival and proliferation, contributing
significantly to disease progression.
As the disease advances to more aggressive stages, additional genetic alterations accumulate.
TP53 mutations become more frequent, leading to disrupted cell cycle regulation and
increased genomic instability [32]. The tumor microenvironment undergoes significant
changes, with increased inflammation and altered extracellular matrix composition. These
changes facilitate tumor growth and eventual metastasis [33]. The expression of various
growth factors, particularly VEGF, promotes angiogenesis, which is crucial for tumor
expansion and spread [34].
In advanced stages, prostate cancer frequently develops resistance to androgen deprivation
therapy, leading to castration-resistant prostate cancer (CRPC). This resistance often develops
through multiple mechanisms, including AR splice variants, increased AR sensitivity, and
alternative androgen synthesis pathways [35]. The metastatic process preferentially targets
bone tissue, where complex interactions between tumor cells and the bone microenvironment
lead to the establishment of metastatic lesions. This process involves the activation of
osteoblasts and osteoclasts, resulting in the characteristic osteoblastic metastases seen in
prostate cancer [36].
Figure 1. Pathophysiology of Prostate cancer
DRUG CHOICE FOR PROSTATE CANCER
Ormeloxifene
Ormeloxifene, may inhibit EMT by repressing N-cadherin and β-catenin/TCF-4
transcriptional activity. Ormeloxifene has already been reported to demonstrate anti-cancer
activity in different carcinoma such as ovarian, head and neck, and breast. However, Hafeez
et al. (2017) studied ormeloxifene for the treatment of PCa and explained its effects on EMT
processes and Wnt/β-catenin signalling. To validate their hypothesis, they used molecular
docking as an in silico validation method and ormeloxifene showed proficient docking with
β-catenin and GSK-3β. In addition, in vitro cell culture studies showed that ormeloxifene
induced apoptosis, and reduced tumorigenic, metastatic, and invasive potential of PCa cells.
Moreover, treatment remarkably reduced the prostate tumor growth in the xenograft mouse
models as in vivo validation for effects of ormeloxifene [37].
Abiraterone acetate
The latest approvals include abiraterone acetate, enzalutamide and apalutamide which target
androgen receptor (AR) signaling, radium-223 dichloride for reduction of bone metastases,
sipuleucel-T immunotherapy and taxane-based chemotherapy. Adding abiraterone acetate to
androgen deprivation therapy (ADT) in order to achieve complete androgen blockade has
proven highly beneficial for treatment of locally advanced prostate cancer and metastatic
hormone-sensitive prostate cancer (mHSPC). Also, ADT together with docetaxel treatment
showed significant benefit in mHSPC [38].
NSAIDs and COX-2 inhibitors
In animal studies, several NSAIDs stimulate apoptosis in prostate cancer cells. Selective
COX-2 inhibitors such as NS398 and celecoxib induce apoptosis in prostate cancer cells, but
not in normal cells. COX-2 is also implicated in angiogenesis; COX-2 overexpression
induces the production of vascular endothelial growth factor (VEGF), suggesting that COX-2
promotes progression, in part, by inducing angiogenesis. NS398 inhibits VEGF production
and decreases angiogenesis in PC-3 prostate cancer cells [39].
Calcium Channel Blockers (CCBs)
Studies have shown that CCBs, particularly nifedipine and amlodipine, may inhibit prostate
cancer cell proliferation by disrupting calcium-dependent signaling pathways crucial for
cancer cell survival. Research indicates these drugs can induce apoptosis in prostate cancer
cells while showing minimal toxicity to normal cells [40].
ACE Inhibitors and ARBs
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers
(ARBs) have demonstrated potential in reducing prostate cancer progression. Clinical studies
suggest these medications may decrease tumor angiogenesis and metastasis by modulating
the renin-angiotensin system [41].
Beta-Blockers
Propranolol and other beta-blockers have shown promise in reducing prostate cancer
metastasis by blocking stress-induced signaling pathways. These drugs may inhibit cancer
cell migration and invasion through β-adrenergic receptor antagonism [42].
LIMITATIONS OF MODERN TREATMENT METHODS
Although chemotherapy and radiotherapy are highly effective methods of cancer treatment,
these methods exert severe side effects in use. One of the main problems in cancer treatment
is gradual resistance of cancer cells against treatment. Hence, achieving a new approach is
one of the aims of immuno pharmacological studies to improve cancer treatment results.
From 1980 to 2000, following Aristotle and Jalinos doctrine, indicating cancer as a result of
black bile coagulation, up to now during which with the advent of new treatment methods,
cancer mortalities have been reduced for 25%, plants have played an important role in
controlling cancer symptoms and treatments [43].
HERBAL IMPORTANCE
From 200 to 1800 AD, following the teachings of Aristotle and Galen, which was
believed that cancer, was a consequence of the coagulation of “black bile” till now when
prevalence of biology has contributed to a 25% reduction in mortality, herbs play an
important role in cancer symptom management, patients' quality of life and survival.
The main objectives of herbal therapies are:
Primary prevention of cancer; this is important for those who have a strong family
history of cancer.
Secondary presentation; prevention of a recurrence of cancer is therefore the objective
for this group.
To enhance body's immune system.
To reduce the side effects resulting from conventional therapies such as chemotherapy
or radiation therapy.
In advanced stages of cancer, when conventional therapies have failed, many patients
have no choice but resort to alternative treatments.
The way herbal medicine fight cancer is significantly different from conventional chemical
drugs, where no DNA mutation in surviving cell occurs. Specifically, natural compounds
fight cancer by strengthening the immune system preventing the spread of cancer cells
through inhibition of angiogenesis or growth of new blood vessels feeding the cancer cells,
detoxifying the body and preventing further toxic build-up in the body, Reducing free radical
formation which cause mutational changes that lead to cancer formation and supporting all
targeted organs, especially those affected directly by the cancer. Besides creating an
unfavourable environment for cancer growth is another benefit of herbal medicines, where,
the ideal environment creates a high level of oxygen and temperature including increased
metabolism rate, low sugar level and a high alkalinity space in the body [43].
IN SILICO STUDIES
In silico studies represent computational approaches in drug discovery that utilize various
software tools and algorithms to predict, analyse, and simulate molecular interactions. These
methods have become increasingly important in modern drug development due to their cost-
effectiveness and ability to streamline the drug discovery process [44].
Key Components of In Silico Studies:
1. Database Mining and Virtual Screening: Utilization of chemical databases (PubChem,
ChEMBL), Structure-based virtual screening, Ligand-based virtual screening,
Machine learning approaches for compound selection [45].
2. Molecular Modelling: Protein structure prediction, Homology modelling, Ab initio
modelling, Molecular dynamics simulations [46].
3. Molecular Docking: Rigid docking, Flexible docking, Ensemble docking, Scoring
functions and binding energy calculations [47].
4. ADMET Prediction: Absorption prediction, Distribution analysis, Metabolism
assessment, Excretion patterns, Toxicity prediction [48]
5. Quantitative Structure-Activity Relationship (QSAR): 2D QSAR studies, 3D QSAR
analysis, Pharmacophore modelling, Activity prediction [49]
IN VITRO STUDIES
In vitro studies represent a fundamental approach in biomedical research, particularly in drug
discovery and development, where experiments are conducted in a controlled laboratory
environment using isolated components of living organisms. These studies serve as essential
preliminary investigations before proceeding to more complex in vivo experiments. In the
context of drug development, in vitro studies typically involve the use of cultured cells,
tissues, or biochemical components to evaluate the biological activity, mechanism of action,
and potential toxicity of test compounds [51].
For example, when studying the anticancer potential of a newly isolated plant compound,
researchers might begin by testing its effects on cancer cell lines such as MCF-7 (breast
cancer), HeLa (cervical cancer), or A549 (lung cancer) cells. The investigation would
typically start with cell viability assays such as MTT or SRB assays to determine the
compound's cytotoxicity and IC50 values. Following this initial screening, more detailed
mechanistic studies might be conducted to understand how the compound affects cancer
cells, including cell cycle analysis using flow cytometry, apoptosis detection through
techniques like Annexin V staining, and investigation of protein expression changes using
Western blot analysis [52,53].
In vitro studies also play a crucial role in understanding drug resistance mechanisms and
developing combination therapies. For instance, researchers might use resistant cell lines to
study how cancer cells evade treatment and test various drug combinations to overcome this
resistance. These studies typically involve long-term culture experiments, gene expression
analysis, and detailed biochemical assays to elucidate the molecular pathways involved in
drug resistance and sensitivity [54].