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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_6035_Библиотеки_им_академика_М_И_Перельмана.pdf
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activators of transcription (STAT) proteins inhibit apoptosis and promote the development
of cancer cells. Members of this family of proteins are inhibited by MLF and AIF because
they are not phosphorylated, which is necessary for the survival of cancer cells (Kumar,
2013). Moreover, avonoids block the expression of nuclear factor kappa B (NF-kB),
which is essential for the survival, angiogenesis, and proliferation of cancer cells.
6.2.3 BRASSINOSTEROIDS
BRs are naturally occurring compounds found in plants, serving multiple functions such
as regulating hormone signaling to control cell development and differentiation, elongating stem and root cells, and providing resistance against both biotic and abiotic stress.
Additionally, BRs are utilized to manage plant senescence. They are necessary for the
growth and development of plants. BRs are another naturally occurring substance that has
shown therapeutic value to fight against cancer.
In a study conducted by Malíková et al. (2008), two naturally occurring BRs, 28-homocastasterone (28-homoCS) and 24-epibrassinolide (24-epiBL), were utilized to investigate
their anticancer potential against malignant cells. These compounds demonstrated anticancer effects, even at micromolar concentrations, across various cancer cell lines. Cancer
cells have a fundamental inability to undergo apoptosis and an unending capacity for
proliferation. Through interaction with the cell cycle, BRs can trigger reactions essential
for growth inhibition and apoptosis. BRs have been applied to treat a diverse range of
cancer cell lines, which include T-lymphoblastic leukemia CEM, multiple myeloma RPMI
8226, cervical carcinoma HeLa, lung carcinoma A-549, osteosarcoma HOS, as well as
prostate cancer and breast cancer cell lines (Panibrat et al., 2019).
6.2.4 VINCA ALKALOIDS
The initial drugs utilized in therapeutics were vinca alkaloids, derived from Catharanthus
roseus G. Don. This included vinblastine (VLB) and vincristine (VCR). These medications
were found during a search for oral hypoglycemic agents. In their research, scientists
observed that these plant extracts caused a significant reduction in white blood cell count
and induced bone marrow depression in rats. However, they were unable to explain the
mechanism behind these effects. Additionally, the plant extract was found to extend the
lifespan of mice with transplantable lymphocyte leukemia. VCR and VLB, two active
alkaloids, were ultimately isolated by further extraction and fractionation (Dhyani et al.,
2022). Vinorelbine and vindesine are recent examples of vinca alkaloid semisynthetic
counterparts. VLB is employed in the treatment of various cancers, either as a standalone
medication or in combination with other chemotherapeutic agents. Conditions such as
lymphoma leukemia, lung cancer, Kaposi's sarcoma, breast cancer , and testicular cancer are
among those treated with VLB. Moreover, VCR has shown effectiveness against leukemia,
particularly juvenile acute lymphocytic leukemia.
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6.2.5 TAXANES
Taxanes include a group of compounds used to develop chemotherapeutic drugs. A
significant and sustainable natural source of this important class of drugs is paclitaxel
(now known as taxol), which is found in the leaves of several Taxus
species (Sayed et al.,
2020). Initially , the bark of T axus br evifolia was used to extract paclitaxel. Active paclitaxel
analog, such as docetaxel (T axotere), is also readily converted from the relatively abundant
baccatin which is a group of chemical compounds found in the bark of Pacific yew tree.
This compound is the precursor of taxanes production through semisynthetic paclitaxel
synthesis in addition to its application in treating a broad spectrum of malignancies like
Kaposi sarcoma, paclitaxel has demonstrated efficacy in addressing breast, ovarian, and
non-small-cell lung cancer as well. It has also received interest because of its potential to
treat rheumatoid arthritis, multiple sclerosis, and psoriasis.
6.2.6 CAMPOTHECIN DERIVATIVES
The family of clinically active medicines developed from camptothecin represents another
development in the field of anticancer medication. Camptothecin was originally extracted from
the Chinese ornamental tree Camptotheca acuminate Decne (Nyssaceae), often known as the
“tree of gladness.” Out of 1000 different plant extracts examined for antitumor activity, only
the extract of C. acuminates showed effectiveness. The active component responsible for the
antitumor activity was identified as camptothecin. The National Cancer Institute began using
camptothecin in clinical studies in the 1970s, but it was quickly discontinued due to concerns
about serious bladder damage. Extensive studies were carried out, and the company named
Glaxo SmithKline created T opotecan (Hycamtin), a camptothecin derivative that was developed
during a quest by numerous groups for more potent derivatives with anticancer properties.
The structures of few plant-derived anticancer agents are depicted in Figure 6.1.
6.3 MICROORGANISMS-BASED ANTICANCER COMPOUNDS
Many microorganisms consist of anticancer properties that include bacteria, fungi, and
viruses, and these belong to primary and secondary metabolites. Some are
l-asparaginase,
arginine, actinomycin D, bleomycin, anthracyclines, enediynes, MMC, epothilones, calicheamicin, and mithramycin A. These are in clinical use, and there are other compounds
also; they are in the development and research stage.
6.3.1 PRIMARY METABOLITES
There is a vast variety of
l-asparaginase enzymes (E.C.3.5.1.1) in plants, animals, and
microbes. It was discovered that Escherichia coli, Erwinia carotovora, and Bacillus sp.
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were the most often employed microbes for producing l-asparaginase (Moharib, 2018).
These have anticancer properties, and this natural enzyme is utilized in cancer treatment,
particularly in acute lymphoblastic leukemia (ALL), owing to its ability to deplete asparagine levels in the bloodstream (Muneer et al., 2022). Many cancer cells heavily rely on
external sources of asparagine for survival and growth. By catalyzing the hydrolysis of
asparagine, l-asparaginase effectively starves these cancer cells, hindering their proliferation and inducing cell death. The enzyme’s selective targeting of cancerous cells makes
it a valuable component of chemotherapy regimens, improving survival rates for patients
with certain types of cancer (Hassan et al., 2018). As research continues, l-asparaginase
(Figure 6.2) remains a promising avenue for combating cancer and enhancing treatment
outcomes.
FIGURE 6.1 Structures of plant-derived anticancer agents.
FIGURE 6.2 L-asparagine.
⏎
⏎
One of the mechanisms causing tumor growth is arginine metabolism (Figure 6.3),
which is highly compartmentalized since different cell types produce arginine
metabolism-related enzymes.
l-arginine is a versatile amino acid that is also a source
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of many metabolites, such as polyamines and nitric oxide, which are both potent
immunomodulators (Popolo et al., 2014; Roszik et al., 2018). However, research has
focused on certain microorganisms that produce arginine-depleting enzymes, such as
l-arginine deiminase (ADI) is produced by some microorganisms, such as Mycoplasma
spp. and Pseudomonas aeruginosa, that depletes arginine levels in the blood. ADI-
based therapies have shown promising results in inhibiting tumor growth and inducing
cancer cell death in preclinical studies. Clinical trials are ongoing to further explore the
potential of arginine-depleting enzymes as a targeted anticancer strategy (Zare-Zardini
et al., 2018). Nevertheless, it is important to note that more research is needed to fully
understand the safety and efficacy of these treatments before they can be widely used
in clinical practice. In recent times, bacteria depending on cancer immunotherapy have
rich pathogen-associated molecular patterns in anticancer abilities in immune responses
(Thakker and Narayanan, 2023).
FIGURE 6.3 Arginine.
⏎
6.3.2 SECONDARY METABOLITES
Actinomycin is a class of antibiotics found in numerous species of soil-dwelling bacteria,
particularly in Streptomyces strains. Within this class, two major compounds, known as
actinomycin A and actinomycin B, have been identified. The discovery of actinomycin
and its compounds is credited to the pioneering work of Dr. Selman A. Waksman and
his team in 1940. Dr. Waksman, an esteemed microbiologist often hailed as the “Father
of Antibiotics,” isolated these substances from the soil bacteria, opening new avenues
for antibiotic research and revolutionizing medical science. In 1952, actinomycin C
became the first crystalline antibiotic, facilitating detailed studies. It also showed
significant in vitro antitumor activity, holding promise for cancer treatment advance-
ments (Waksman and Woodruff, 1940; Hackmann, 1952). In 1963, actinomycin D
(Figure 6.4) was approved for the treatment of highly malignant tumors. It is composed
of a planar 2-aminophenoxazin-3-one chromophore and two large cyclic pentapeptide
lactones. Actinomycin D has also been isolated from a marine-derived strain (Strepto-
myces sp.
MS449) from the South China Sea (Chen et al., 2012). According to a recent
source, researchers have explored a novel approach by combining two anticancer DNA
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intercalators: actinomycin D and echinomycin, both of which are natural antibiotics
produced by Streptomyces species. This innovative combination has shown potential in
cancer treatment and merits further investigation (Satange et al., 2023); the mechanism
is depicted in Figure 6.5.
FIGURE 6.4 Actinomycin D.
FIGURE 6.5 Mechanism of actinomycin D against cancer.
⏎
⏎
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Bleomycin has a core structure that is a complex polypeptide chain made up of multiple
amino acids (Figure 6.6) but differs based on various positively charged functional groups
and disaccharides. These were isolated from Streptomyces verticillus by Umezawa’s group
at the Institute of Microbial Chemistry , T okyo, and developed as anticancer agents by Bristol
Myers (Hecht, 1986). It is used in the treatment of squamous cell carcinomas, germ cell
tumors, and lymphomas (Stubbe and Kozarich, 1987). The mechanism of action of bleomycin involves oxidative cleavage of DNA and possibly RNA degradation (Akiyama et al.,
2008). Recent findings reveal that the newly discovered bleomycin antibiotic, NC-0604,
demonstrates enhanced cytotoxicity in Streptomyces verticillus var. pingyangensis n. sp.
Additionally, compared with traditional bleomycin, NC-0604 shows increased cytotoxic
effects on various human tumor cell lines. These promising results open up new possibilities
for potential medical applications and warrant further investigation (Chen et al., 2008). The
mechanism of bleomycin is illustrated in Figure 6.7. In recent years, electrochemotherapy
utilizing bleomycin has proven to be a successful treatment for various skin cancers. The
use of microsecond electrical pulses significantly improves the delivery of bleomycin and
enhances its anticancer effectiveness (Tunikowska et al., 2023).
FIGURE 6.6 Bleomycin.
⏎
The most important anthracyclines are daunorubicin and DOX (Figure 6.8) for cancer treatment. Daunorubicin is used to treat acute lymphoblastic or myeloblastic lymphoma, and
DOX is used to treat breast cancer, pediatric solid tumors, soft tissue sarcoma, and advanced
lymphoma (Krohn, 2008). DOX, originally isolated from Streptomyces peucetius in 1974,
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was initially utilized in the USA for cancer treatment. This anthracycline chemotherapy
drug has proven effective in treating a range of cancers, including breast cancer, ovarian
cancer, lymphomas, and certain pediatric cancers. By inhibiting cancer cell growth and
replication, DOX aids in slowing or halting the advancement of the disease (Khazir et al.,
2014). The mechanism of action of DOX includes intercalation between the base pairs
of the DNA strands and inhibition of the synthesis of DNA and RNA; the generation of
iron-mediated free radicals, causing oxidative damage to the cellular membrane, protein,
and DNA (Shaik et al., 2022) (Figure 6.9). Deoxy glucose, after proper modification by a
glycosyltransferase (GT), is important for the biology and biochemistry of many bacterial
natural products. These enzymes, known for their crucial roles in biosynthesis, have also
shown potential in cancer research due to their involvement in cancer-related processes.
However, the quest for more active GT remains vital to unlock their full potential in developing novel anticancer therapies (Yang et al., 2023).
FIGURE 6.7 Mechanism of bleomycin against cancer.
FIGURE 6.8 Doxorubicin and daunorubicin.
⏎
⏎
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FIGURE 6.9 Mechanism of anthracyclines against cancer.
⏎
Enediynes represent a distinctive class of antitumor antibiotics, characterized by their
unique structure (Figure 6.10). Calicheamicin γ1′, among the most significant approved
microbial compounds, is the 10-membered ring calicheamicin, which was initially isolated
in 1987 from the bacterium Micromonospora echinospora
spp. calichensis (Hamann et al.,
2005). The terminal nucleus consists of two acetylene groups linked through a double bond
within a 9 or 10-membrane ring (Hamann et al., 2012). In the year 2000, the FDA granted
approval for gemtuzumab ozogamicin, which is a humanized anti-CD33 antibody linked to
a semisynthetic calicheamicin derivative. It became the first antibody warhead conjugate
sanctioned for the treatment of chronic myelogenous leukemia. It is probably the most
powerful antitumor drug approved (Herbertson et al., 2009). It is characterized structurally
by a 1,5-diyn-3-ene motif within the 9 or 10-membered enediyne core. Anthraquinone
fused enediynes belong to a class of 10-membered enediynes that incorporate an anthraquinone unit fused to the enediyne nucleus, exemplified by dynamin and tiansimycin. The
conserved type 1 repetitive polyketide synthase (PKSE) has been identified as the key
enzyme responsible for initiating the biosynthesis of all enediyne cores. Recent evidence
suggests that the anthraquinone moiety is also derived from the product of PKSE. These
discoveries hold great promise in the field of cancer research, as enediynes and anthraquinones have shown potent anticancer properties. Understanding the biosynthetic pathways
can pave the way for developing novel and more effective anticancer therapies based on
these natural compounds (Bhardwaj et al., 2023).
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FIGURE 6.10 Enediyne.
⏎
MMC (Figure 6.11), an anticancer antibiotic developed by Streptomyces caespitosus
species in the 1950s, works by inhibiting DNA synthesis and causing damage to DNA. It
finds application in the treatment of various cancers, such as cervix, breast, head, anal, liver,
bladder, colorectal, lung, pancreatic, and stomach cancers. MMC Kyowa and Mitomycin
Accord are available commercially (Crooke and Bradner, 1976). DOX and MMC had
an additive impact on murine breast cancer cells when used in vitro. DOX-loaded solid
polymer–lipid hybrid nanoparticles had increased the efficacy and decreased the systemic
toxicity when used in animal models of breast cancer (W arren et al., 2001; Shuhendler et al.,
2010). Methanolic extracts from 60.8% of the strains exhibited strong antimicrobial activity
against Staphylococcus aureus, Micrococcus gluteus, Bacillus subtilis, E. coli, Salmonella
enterica, and Saccharomyces cerevisiae, as well as the PC3 (prostate cancer) and A549
(lung carcinoma) cell lines. Currently , ef forts are underway to scale up the fermentation of
the anti-Gram-negative strain PU-KB10 (Streptomyces griseoviridis) due to its promising
antimicrobial properties (Saleem et al., 2023).
FIGURE 6.11 Mitomycin C.
⏎
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In the mid to late 1980s, Reichenbach and Hoefle discovered the 16-membered macrolide
epothilones A and B (Figure 6.12) from the Sorangium cellulosum strain So ce90. These
compounds exhibited tubulin-stabilizing activity, similar to that of paclitaxel, leading to
increased interest in chemical, biochemical, and genomic modifications to explore the
potential of the epothilone base skeleton further (Reichenbach and Hoefle, 2008). Following
FDA approval, Bristol-Myers developed 17-aza-epothilone B, a semisynthetic epothilone
with an amide linkage replacing the lactone bridge, for breast cancer treatment. In preclinical
studies, epothilone A showed lower activity compared with epothilone B, which extended
to more advanced clinical research stages. Surprisingly, the sole difference between these
12
two molecules is the inclusion of a methyl group at C
(Kowalski et al., 1997). For the
treatment of ovarian cancer, Epothilone B was in Phase III clinical trials, but Novartis
Oncology stopped these studies in 2010 since the drug failed to show a meaningful overall
survival advantage (Ferrandina et al., 2012). The analogs of epothilone include ixabepilone,
sagopilone, 21-amino-epothilone B, and KOS-1584 (Valentová et al., 2023). Epothilone
exerts its action by inducing tubulin polymerization and apoptosis, displaying a similar
mechanism to paclitaxel. It demonstrates enhanced effectiveness compared with paclitaxel
in cancer treatment while remaining less susceptible to tumor resistance mechanisms. Since
its discovery, various derivatives have been developed, but only ixabepilone has found use
in clinical practice due to the failure of most others in Phase II and III of clinical trials
(Villegas et al., 2023).
FIGURE 6.12 Epothilone B.
⏎
6.4 SELECTED MEDICINAL PLANTS WITH ANTICANCEROUS ACTIVITIES
6.4.1 CURCUMA LONGA L.
Curcuma longa, known as turmeric, is a fragrant therapeutic plant that has been widely
used in Indian traditional medicine (Ayurveda) to treat a variety of illnesses. Turmeric
contains curcumin, a polyphenol that is responsible for the potent anticancer effects against