CC BY
6Received by the Editor 27.02.2020
IRSTI 76.29.49+76.31.31
GENERAL CHARACTERISTICS OF THE EFFECTIVENESS OF THE USE OF MEDICINAL PLANTS FOR CANCER
G. Yestemirova1, Z. Yessimsiitova1, G. Sitpayeva2
1Al-Farabi Kazakh National University, Almaty city, Kazakhstan
2Institute of botany and phytointroduction CS MES RK, Almaty city, Kazakhstan
Humanity has seen many terrible diseases in the form of plague, leprosy, smallpox, Spanish flu, anthrax. Modern medicine has dealt with many of them. The XX-XXI century is the time of the rapid development of medicine, which is able to save from many ailments. However, there are diseases such as cancer, which remain at the beginning of this millennium one of the most complex and pressing problems of humanity. This pathology occupies one of the leading places in the overall morbidity structure. Statistics give horrific figures - every minute in the world 2 people die from cancer. According to the World Health Organization (WHO), cancer is a non-communicable disease that accounts for 63% of deaths worldwide. This makes cancer an important health problem that requires exploring new strategies for disease prevention and treatment. Natural therapies, such as using plant products in cancer treatment, can reduce side effects. Plants have been used for medical purposes since the beginning of human history and are the foundation of modern medicine. Most chemotherapeutic drugs for treating cancer are molecules identified and isolated from plants or their synthetic derivatives. Further research is needed to determine the effectiveness of these herbal products in treating cancer in humans. Medicinal plants and biologically active substances isolated from them often exhibit high immunotropic and antitumor activity. The article shows the characteristic features of research experimentally confirm those properties of plants that were known in traditional medicine and have actually been used.
Keywords: oncology, cancer, anticancer, medicinal plants, alternative medicine, pharmacology.
ОБЩАЯ ХАРАКТЕРИСТИКА ЭФФЕКТИВНОСТИ ПРИМЕНЕНИЯ ЛЕКАРСТВЕННЫХ РАСТЕНИЙ ПРИ ОНКОЛОГИЧЕСКИХ ЗАБОЛЕВАНИЯХ
Естем1рова Г.Э.1, Есимсиитова З.Б1, Ситпаева Г.Т.2
1Казахский национальный университет имени аль-Фараби, Алматы, Казахстан
^Институт Ботаники и Фитоинтродукции КН МОН РК, Алматы, Казахстан
Человечество видело множество страшных болезней в виде чумы, проказа, оспы, испанки, сибирской язвы. Со многими из них современная медицина справилась, ХХ-ХХ1 век является, временим стремительного развития медицины, которая способна спасти от множества недугов. Однако есть такие болезни, как онкологические заболевания, которые остаются и в начале нынешнего тысячелетия одной из самых сложных и актуальных проблем человечества. Эта патология занимает одно из ведущих мест в общей структуре заболеваемости. Статистика приводит ужасающие цифры - каждую минуту в мире от рака умирают 2 человека. По данным Всемирной организации здравоохранения (ВОЗ), рак представляет собой неинфекционные заболевания, которые являются причиной 63% смертей во всем мире. Это делает рак важной проблемой для здоровья, которая требует исследовать новые стратегии по профилактике и лечению заболеваний. Природные методы лечения, такие как использование растительных продуктов в лечении рака, могут уменьшить побочные эффекты. Растения использовались в медицинских целях с начала человеческой истории и являются основой современной медицины. Большинство химиотерапевтических препаратов для лечения рака представляют собой молекулы, идентифицированные и выделенные из растений или их синтетических производных. Необходимы дальнейшие исследования для определения эффективности этих растительных продуктов при лечении рака у людей. Лекарственные растения и биологически активные вещества, выделенные из них, нередко обнаруживают высокую иммунотропную и противоопухлевую активность. В статье показаны характерные особенности исследований экспериментально подтверждаются те свойства растений, которые были известны в народной медицине и фактически уже использовались.
Ключевые слова: онкология, опухоль, антиопухоль, лечебные растения, альтернативная медицина, фармакология.
ОНКОЛОГИЯЛЬЩ АУРУЛАР КЕЗ1НДЕ ДЭР1Л1К 0С1МД1КТЕРД1 ПАЙДАЛАНУ ТШМДЫЮНЕ ЖАЛПЫ СИПАТТАМА
Естем1рова Г.Э.1, Есимсиитова З.Б.1, Ситпаева Г.Т.2
1эл-Фараби атындагы казак улттьщ университет^ Алматы к;., ^азакстан
2КР БЕМ ЕК Ботаника жэне фитоинтродукция институты, Алматы ^азакстан
Адамзат оба, алапес, шешек, испан т^мауы, ci6ip жарасы icnerrec кептеген коркынышты ауруларды керген болатын. Каярп замангы медицина олардын кепшiлiгiнiн емш тапты. ХХ-ХХ1 гасыр - кептеген аурулардан к¥™луга мYмкiндiк беретiн медицинанын каркынды даму кезенi. Алайда катерл iciK сиякты аурулар казiрri мьщжылдыктьщ басында адамзат Yшiн ен кYрделi жэне езектi мэселелерiнiн бiрi болып кала береди Б^л патология жалпы сыркаттанушылык к¥рылымында жетекшi орындардын бiрiн алады. Статистика жан^шырарлык сандарды керсетуде - элемде эр минут сайын 2 адам катерл iсiктен кайтыс болады. ДYниежYзiлiк денсаулык сактау ^йымыньщ (ДДС¥) мэлiметтерi бойынша, катерл iсiк - 6ym элемде елiмнiн 63% к¥райтын ж^кпалы емес ауру. Б^л - катерл iсiк ауруларынын алдын алу мен емдеудiн жана стратегияларын зерттеудi кажет ететiн манызды денсаулык сактау мэселесше айналдырады. 9сiмдiктер адамзат тарихында медициналык максатта колданылган жэне казiргi медицинанын негiзi болып табылады. Табиги терапия, мысалы, есiмдiктерден алынатын енiмдердi катерлi iсiк ауруын емдеуде жанама эсерлердi азайтуга болады. Кдгерл гакп емдеуге арналган химиотерапиялык препараттардын кепшшп есiмдiктерден немесе олардын синтетикалык туындыларынан алынган жэне окшауланган молекулалар болып табылады. всiмдiк енiмдерiнiн катерлi южп емдеудегi тиiмдiлiгiн аныктау Yшiн косымша зерттеулер кажет. Дэрiлiк есiмдiктер мен олардан окшауланган биологиялык белсендi заттар кебшесе жогары иммунотропты жэне юшке карсы белсендiлiктi керсетедi. Макалада зерттеудщ сипаттамалык белгiлерi дэстYрлi медицинада белгш болган жэне iс жYзiнде колданылган еамджтердщ касиеттерiн экспериментальды тYPде растайды.
ТYЙiн свздер: онкология, iсiк, антшсж, дэрiлiк есiмдiктер, баламалы медицина, фармакология.
Introduction
One of the most actively developing areas of medicine is biological cancer therapy - hightech methods of treatment, including exposure to the patient's natural defense mechanisms or the introduction of substances of natural origin. The healing properties of medicinal plants are due to active or pharmacologically active substances - alkaloids, glycosides, saponins, tannins, enzymes, vitamins, hormones, volatile production. They are the most valuable, although they are contained in plants in small quantities. Taken internally or externally, these substances help the sick body cope with the disease. More recently, in the minds of our contemporaries, medicinal plants have been associated with a relic of ancient times. Indeed, it is difficult to combine our century of scientific and technological revolution with a bunch of dried herbs, from which in the past mankind with blind faith expected miraculous healings.
Cancer can begin almost anywhere in the human body. In all types of cancer, some of the body's cells begin to divide without stopping and spread into surrounding tissues. In general, cancer must reach a size of 1 cm, or be comprised of 1 million cells, before it is detected. At this point, it may be referred to as a "'mass," a "growth," a "tumor," a "nodule," a "lump," or a "lesion." Exceptions to this general rule include cancers of the blood and bone marrow (leukemia's and lymphomas) - which frequently do not produce a "mass," but will be evident on laboratory tests [1]. Cancer cells differ from normal cells in many ways that allow them to grow out of control and become invasive.
For today cancer considered as one of the most prevalent diseases in the world, and its mortality is increasing. The global cancer burden has risen to 18.1 million cases and 9.6 million cancer deaths in 2018 [2]. The reasons are complex but reflect both aging and growth of the population, as well as changes in the prevalence and distribution of the main risk factors for cancer [3]. In the low- and middle-income countries, the picture is even darker, where approximately 70% of deaths are due to cancer diseases and where only one in five countries have the necessary data to drive cancer policy [4]. Advancing the fight against cancer requires both increased investment in cancer pathology research and in new safe, effective, inexpensive and minimal side effect anticancer agents. One important difference is that cancer cells are less specialized than normal cells. That is, whereas normal cells mature into very distinct cell types with specific functions, cancer cells do not. This is one reason that, unlike normal cells, cancer cells continue to divide without stopping. In addition, cancer cells are able to ignore signals that normally tell cells to stop dividing or that begin a process known as programmed cell death, or apoptosis, which the body uses to get rid of unneeded cells. Cancer cells may be able to influence the normal cells, molecules, and blood vessels that surround and feed a tumor—an area known as the microenvironment. For instance, cancer cells can induce nearby normal cells to form blood vessels that supply tumors with oxygen and nutrients, which they need to grow. These blood vessels also remove waste products from tumors. Cancer cells are also often able to evade the immune system, a network of organs, tissues, and specialized cells that protects the body from infections and
other conditions. Although the immune system normally removes damaged or abnormal cells from the body, some cancer cells are able to "hide" from the immune system. Tumors can also use the immune system to stay alive and grow. For example, with the help of certain immune system cells that normally prevent a runaway immune response, cancer cells can actually keep the immune system from killing cancer cells.
The appointment of herbal remedies to cancer patients is carried out on the basis of clinical data and the known pharmacotherapeutic properties of plants. A wide range of herbal remedies is used with pronounced cytostatic, antimicrobial, immunotropic, detoxification, anti-inflammatory, hemostatic and reparative effects. Often phytotherapeutic care for cancer patients is necessary and appropriate. It should be emphasized that herbal medicine is not opposed to the achievements of science, but complements the treatment of cancer patients. The development of cancer registries throughout the world has led to a search for novel drugs that are toxic to the cancer cells while having no harmful effect on normal cells. Natural therapies, such as the use of plant-derived products in cancer treatment, may reduce adverse side effects. Plants/herbs have been used for medical purposes since the beginning of human history and are the basis of modern medicine.
The World Health Organization (WHO) estimates that 80% of the population of developing countries relies on traditional medicine for their primary care needs [5]. With due attention to rapid progress in the phytochemical study of plants/herbs, they are becoming popular because of their anticancer effects.
The drugs developed by synthesis and used in chemotherapy have limitations mainly due to their toxic effects on non-targeted tissues and consequently furthering human health problems. Therefore, there is a demand for alternative treatments, and the naturally-derived anticancer agents are regarded as the best choice. Herbal remedies were the first medicines used by humans due to the many pharmacologically active secondary metabolites produced by plants [6]. Plants have served as medicine throughout human history. Since the passage of the Dietary Supplement Health and Education Act (DSHEA), inconsistent regulatory practices have resulted in widespread, indiscriminate use of herbal supplements. Available data indicate that cancer patients use these products (along with standard treatments) more often than the general population. The reasons cited for such use include improving health, reducing the risk of recurrence, and reducing the side effects of cancer treatments. Herbs, however, contain biologically active compounds and can potentially interact with prescription medications, including chemotherapy drugs [7].
For millennia, indigenous cultures around the world have used traditional herbal medicine to treat a myriad of maladies. Plants constitute a common alternative for cancer treatment in many countries, and more than 3000 plants worldwide have been reported to have anticancer properties [8]. Although a recent study suggests that nowadays, the traditional medicines are less used, even in populous middle-income countries [9]. In the last two decades, the use of herbal remedies has also been widely embraced in many developed countries as complementary and alternative medicine, but following tight legislation and under surveillance [10]. Natural products have garnered increasing attention in cancer chemotherapy because they are viewed as more biologically friendly and consequently more co-evolved with their target sites and less toxic to normal cells [11]. Moreover, there is evidence that natural product-derived anticancer drugs have alternative modes of promoting cell death [22-23]. Based on these facts, many researchers are now centering their investigations on the plants' potential to deliver natural products that can become useful to the pharmaceutical industry [12].
Current research in drug discovery from medicinal plants involves a multifaceted approach combining botanical, phytochemical, biological, and molecular techniques. Medicinal plant drug discovery continues to provide new and important leads against various pharmacological targets including cancer [13].
Numerous anticancer drugs isolated from plant materials are tested on cells (including various cancer cell lines) and experimental animals after purification and then sent to clinical trials. In recent years, there has been a dynamic increase in the number of newly discovered natural compounds. In 2006, about 50,000 such substances were known, whereas, in 2014, the number of the newly discovered molecules increased to approximately 326,000. Among these, there were
approximately 170,000 compounds in the toxicity class. In addition, there are 195,000 pharmacologically active compounds for which the interactions are quantitatively known [14]. Plants that have been used in traditional medicine for centuries have found application as sources of materials that possess high biological activity [15]. One approach is to obtain these substances through extractions from the plant materials. The substances of natural origin, e.g., from plants and aquatic animals that exhibit antitumour properties belong to various groups of compounds, such as alkaloids, diterpenes, diterpenoquinone, purine-based compounds, lactonic sesquiterpene, peptides, cyclic depsipeptide, proteins, macrocyclic polyethers, etc.
The following are known anticancer drugs that have been approved for use, as well as new analogies and other less known substances with anti-cancer properties that may be considered as potential chemotherapy drugs. The uses, mechanisms of action, and doses of natural compounds from plants and the marine environment are presented in table 1.
Table 1 - Anticancer effects of natural compounds from plants in different experimental systems.
Natural Compounds
Origin
Cell Line
Dose
Mechanisms of Action
References
Catharanth us
alkaloids
Catharanthus roseus Pink
acute
lymphocytic leukaemia, non-small cell lung cancer, bladder cancer
<1 ^mol
>1-2 ^mol
inhibit the microtubule dynamics and stabilise them disintegrate the microtubules and damage the mitotic spindle, leading to the inhibition of mitosis and causing apoptosis
[16]
Viscum
Album
Extract
Viscum album— Mistletoe plant Viscum
album that are used in therapy are usually a mixture of the extracts
obtained from various host trees (oak, apple, pine, fir, willow, birch, lime, etc.).
human colon cancer cells (Colo 320 HSR)
breast cancer cells (MFM-223, HCC-1937, KPL-1, MCF-7)
10-100 ng/mL
IC50:
VAP-Qu
0.05-0.11
mg/mL
VAP-M
0.10-0.12
mg/mL
VAP-A
0.07-0.31
mg/mL
VAP-P
1.61-2.14
mg/mL
MLI
38-410 ng/mL
activation of the intrinsic (activated Caspase-2 and 9) extrinsic (activated Caspase-2, 3 and 8) pathways of apoptosis
activation of only the mitochondrial pathway of apoptosis
early cell-cycle inhibition followed by apoptosis activation of the mitochondrial pathway of apoptosis
[17,18]
Taxanes
Taxus baccata -European yew Taxus
brevifolia - the Pacific yew
PTX:
breast cancer IC50 of PTX:
cells (MCF-7), HeLa
lung 2.6 nM
adenocarcinoma A549
(A549), cervical 4.1 nM
carcinoma U373
(HeLa), grade III 4.2 nM
astrocytoma MCF-7
(U373), colon 2.5 nM
adenocarcinoma HT-29
(HT-29), 2.8 nM
adenocarcinoma OVG-1
(OVG-1), 4.0 nM
pancreatic PC-Sh
adenocarcinomas 7.5 nM
(PC-Sh) IC50 of DTX:
DTX: A549
human lung 4.26 + 0.51 nM
cancer (A549)
mitosis inhibitors
affect the microtubules
[19,20]
Natural Compounds Origin Cell Line Dose Mechanisms of Action References
Camptothec in Camptotheca acuminata Dec ne (Nyssaceae) human colon HCT116, breast cancer cells (MCF-7), prostate cancer (DU145), leukaemia (CEM) IC50 of CPT: HCT116 169.5 nmol/L MCF-7 180.3 nmol/L DU145 15,700 nmol/L CEM 13,600 nmol/L binds to a complex consisting of DNA and topoisomerase I stabilises the topoisomerase I (TOP1) complex and the ruptured DNA [21]
Combretast atin Combretum caffrum -"African willow" human thyroid papillary carcinoma cell (TPC1) >5 ^M binds to p-tubulin at what is known as the colchicine site causes the destabilisation of the microtubules [22]
Podophyllot oxins Podophyllum peltatum, Podophyllum emodi Podophyllum versipelle, Linum Juniperus small-cell lung cancer (SCLC) >1 Mg/mL (etoposide) disrupt the organisation of the karyokinetic spindle single-strand and doublestrand breaks in DNA through their interactions with DNA topoisomerase II induce cell cycle arrest in the G2-phase of the cell cycle [22]
Geniposide and its derivatives Gardenia jasminoides Ell is—Rubiaceae human non-small-cell lung cancer H1299 cell IC50 of genipin 351.5 |M activation of the mitochondrial execution pathway by Caspase-9 and -3 increase levels of Bax in response to p38MAPK signalling initiation of the mitochondrial death cascade [23]
Colchicine Colchicum gen us (e.g., the autumn crocus, Colchic um autumnale, also known as "meadow saffron") hepatocellular carcinoma HepG2 10 |M depolymerises the microtubules at high concentrations stabilizes the microtubule dynamics at low concentrations limits mitochondrial metabolism in cancer cells [24]
Artesunate Artemisia annua L. medicinal— Asteraceae chronic myeloid leukaemia K562 cells 2 |M antiangiogenic effect inhibits VEGF expression [25]
Homoharrig tonine Cephalotaxus Cephalotaxacea e (C. harringtonia K. Koch, C. haianensis qinensis) gallbladder adenocarcinoma cell line (Mz- ChA-1), colorectal adenocarcinoma cell line (HT-29) Mz-ChA-1 0.1 |M HT-29 1 |M blocks synthesis in the peptidyl transferase centre [26]
Salvicine Salvia pronitis Hance —Labiatae leukaemia cell (P388, HL-60), stomach cancer cell (SGC-7901) IC50: P388 3.49 | M HL-60 3.57 | M SGC-7901 1.84 |M breaks two strands of DNA by facilitating TOP2 activity inhibits re-ligation [27]
Elipticine Ochrosia elliptica Labill leukaemia (HL-60, CCRF-CEM) cells IC50: HL-60 0.64 | M disrupts the cell-cycle by regulating the expression of some kinases (cyclin B1 and [28]
Natural Compounds Origin Cell Line Dose Mechanisms of Action References
CCRF-CEM 4.7 |M Cdc2) generates free radicals
Roscovitine Raphanus sativus L.— Brassicaceae highly metastatic and invasive breast cancer cells MDA-MB231 10 |g/mL inhibits cyclin-dependent kinase (CDK) activity, which preferentially inhibits numerous target enzymes such as CDK1, CDK2 and CDK5 leading to cell-cycle arrest in the G1 and G2 phases [29]
Maytansin Maytenus serrata— Celastracea, Ma ytenus ovatus COLO 205 cells IC50: 0.08 nM inhibits microtubule assembly by binding to tubulin [30]
Tapsigargin Thapsia garganica L.— Apiaceae mouse embryonic fibroblast (MEF) cells 3 |M inhibits sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) in the sarco/endoplasmic reticulum, raises the intracellular calcium concentration, enhances the endoplasmic reticulum stress, caspase activation, releases apoptotic factors from the mitochondria and directly activates the calcium-dependent endonucleases, inhibits the fusion of autophagosomes with lysosomes [31]
Bruceantin Brucea antidysenterica Simaroubacea, Brucea javanica— Fructus Bruceae human pancreatic cancer cells (PANC-1, SW1990) IC50 of Bruceantinosid e A: PANC-1 16.90 |M SW1990 14.08 | M inhibits protein synthesis through interaction with peptidyltransferase, which blocks the formation of peptide binding [32]
IC50—The concentration corresponding to a survival rate of 50% is defined as the IC50.
The main task of herbal medicine is the correct assessment and use of experience accumulated over centuries. Assessing the possibilities of herbal medicine for cancer, we must first focus on the already known pharmacological phenomena and the experience of using antitumor drugs. Modern chemotherapy utilises many substances of plant and aquatic origin. These compounds have cytotoxic properties with many different mechanisms of action, such as the inhibition of tumour cell growth, the induction of apoptosis, DNA damage, the inhibition of topoisomerases I and II, the induction of apoptosis, and others.
Scientific analysis shows that nature contains an unlimited number of chemical compounds that can potentially be used to treat all kinds of human diseases, including oncological ones. Today, the amount of information about medicinal plants significantly exceeds the clinical experience of their use. Medicinal plants and biologically active substances isolated from them often exhibit high immunotropic and antitumor activity. Studies have shown that plant-derived compounds in combination with anticancer drugs have great potential to destroy tumour cells while not affecting normal cells such as lymphocytes and fibroblasts [33]. Logic and experience lead to the conclusion
that it is advisable to search for effective antitumor agents among plants with an antibacterial effect, all the more so since there are enough facts in the literature that indicate antitumor activity of calamus, gingerbread, St. John's wort, calendula, yellow capsule, comfrey, peony, licorice, tatarnik, celandine, eucalyptus, etc. The unifying feature for this group of plants is the presence of an antitumor effect fixed by the people and not refuted by the clinical pharmacology. Most plants can be attributed to biomodifiers, because their antitumor effect is not only cytostatic, but also affects the immune, endocrine systems and other systems and organs due to the induction of protective antitumor reactions. The fact that preparations for use in official oncology have not yet been created from plants does not mean that there will never be such preparations. Medicinal plants of this group may be somewhat inferior in terms of the severity of antitumor effects to such agents as cyclophosphamide or 5-fluorouracil, but relative softness and physiological effects as opposed to chemically aggressive drugs can serve as a reserve for increasing their significance in the treatment of cancer patients.
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Author for correspondence: Estemirova G.Q. - PhD doctoral student of the Department of Biodiversity and Bioresources, Faculty of Biology and Biotechnology, KazNU Al Farabi; e-mail: gulfira.yestemirova@gmail.com
