Introduction
Cancer, a rapid formation of abnormal cells in an uncontrolled manner due to various modifications in gene expression, is one of the leading illness-related deaths worldwide [
1‐
3]. In 2020, it accounted for nearly 10 million deaths globally, comprising a major portion of breast cancer > Lung cancer > Colon and rectum cancer > Prostate cancer > Skin cancer > and Stomach cancer related new cases (
https://www.who.int/news-room/fact-sheets/detail/cancer). Today, chemically derived drugs treatment along with chemotherapy and radiotherapy constitute different components of cancer treatment, with chemo being adverse to healthy cells [
4‐
6]. A comprehensive treatment of cancer is usually available in 90% of high-income countries, but it is only 15% in low-income countries, thus putting a tremendous economic cost on treatment (WHO, 2020). In 2010 alone, the total economic cost of cancer was estimated to be US$ 1.16 trillion [
7]. Nevertheless, many cancers have a high chance of being cured if diagnosed early and treated appropriately [
8,
9]. A 30–50% of cancers can be prevented by avoiding risk factors and implementing evidence-based preventive strategies (
https://www.who.int/news-room/fact-sheets/detail/cancer).
For cancer treatment, plant secondary metabolites as chemo-preventive agents are well classified and recognized as bioactive compounds for primary and secondary prevention [
10‐
12]. Consequently, many pieces of evidence prove that higher consumption of secondary metabolites can lower cancer development [
13,
14]. These compounds have a regulatory effect on metabolic and signaling pathways, thus controlling the angiogenesis, and inhibition of microtubule assembly formation in cells and its apoptosis [
15]. The secondary metabolites can be broadly classified into alkaloids, terpenes, flavonoids, lignans, steroids, curcumins, saponins, phenolics, and glucosides [
16]. These secondary metabolites, either in individuals or in a group can be used for designing personalized cancer prevention programs as these plants based bioactive compounds present much required geno-protective effects such as DNA damage protection in healthy cells [
17‐
19]
.
In the class of phytochemicals, alkaloids have been promising anticancer agents. The alkaloids represent a highly diverse group of compounds, around 3000 distinct alkaloids have been characterized from plants, fungus, and animals together [
20]. Some of the commonly known alkaloids include Morphine and Nicotine [
21]. The alkaloids are low molecular weight organic nitrogenous compounds, often chemically classified into pyrrolidines, pyridines, tropanes, pyrrolizidines, isoquinolines, indoles, quinolines, and terpenoids and steroids. Generally, the alkaloids are colourless, crystalline, and non-volatile (
https://www.britannica.com/science/atropine) and are reported as low in toxicity, with higher stability. It has been found that alkaloids impart a restraining effect on the topoisomerase enzyme, thus stalling DNA replication and cell death [
22]. Therefore, alkaloids have been a base for drug development for various ailments such as anti-inflammatory, antibacterial, and antitumor [
23]. The plant-based alkaloids have proven efficacy in oncogenesis suppression.
This review deals with different anticancer alkaloid compounds viz., (i) colchicine, (ii) vinblastine, (iii) vincristine, (iv) vindesine, (v) vinorelbine, and (vi) vincamine within different domains of existing information on these molecules such as their medical applications (contemporary/traditional), mechanism of antitumor action and potential scale-up biotechnological studies on in-vitro studies. The review shall be a valuable resource for the development of plant-based anticancer therapy, comprising different alkaloids.
Review methodology
Electronic databases such as PubMed/MedLine, Science Direct, and TRIP database have been verified for preclinical pharmacological studies with included molecular mechanisms on the anticancer/cytotoxic/antiproliferative effects of isolated and identified natural alkaloids. Relevant high impact factors have been collected since December 2021. The following MeSH terms were used for the search: “Catharanthus”, “Phytotherapy”, Alkaloids/analysis”, “Alkaloids/isolation and purification”, “Alkaloids/therapeutic use’, “Alkaloids/pharmacology”, “Antineoplastic Agents/pharmacology”, “Apoptosis/drug effects”, “Autophagy/drug effects”, “Benzylisoquinolines/pharmacology”, “Cell Line, Tumor, Cytoprotection/drug effects”, “Humans, Signal Transduction/drug effects”, “Neoplasms/drug therapy”, “Neoplasms/ prevention and control”.
Studies published in English were included, which included plant-derived alkaloids with scientifically identified names, the type of cancer analyzed, the type of cell lines used in experimental pharmacological studies with molecular studies and molecular pathways of action highlighted. Abstracts, conference proceedings, studies that included homoeopathic preparations, and studies that showed pharmacological effects other than anti-cancer were excluded. The taxonomy of plants has been validated using the PlantList [
24,
25].
Design and development of anticancer agents based on natural alkaloids: an overview
The anticancer properties of natural alkaloids have been used traditionally and in contemporary medicine to advance cost-effective overall cancer management. For cancer treatment, researching a natural substance represents an attractive strategy [
139]. As plant-based drug development is advancing due to its proven efficacy and cost-effectiveness, plant alkaloids are the most promising. For the discovery of new natural product-based chemopreventive agents, a judicious selection and a holistic approach for the selection of compound (individual or group), plant source, and plant part are pivotal [
18,
140,
141]. In the scenario of tremendous anthropogenic pressure on natural plant resources and many plant resources coming into the category of “Rare” or “Endangered”, the task of getting the natural compounds becomes a tough job though [
142]. Nevertheless, a sustainable approach regarding anticancer compounds can be, the harvest of novel alkaloid compounds/Biopharmaceuticals from different in-vitro techniques at an industrial scale.
Several drugs have been developed for cancer in recent years, these drugs come with the side-effects along with the development of drug resistance in patients with time [
8,
9,
143,
144]. Therefore, it is difficult to synthesize a chemical-based drug that can distinguish between healthy and tumor cells effectively. Looking at the untoward effects of synthetic drugs, an upsurge, therefore, has been noted in the usage of plant-based drugs in developed and developing countries, mainly due to proven efficacy, safety, lesser side effects, accessibility, and acceptability [
145,
146].
Colchicine is a typical anti-mitotic medication that binds to soluble tubulin to create tubulin-colchicine complexes in a weakly reversible manner, which subsequently adheres to the terminals of microtubules to prevent the microtubule polymer from elongating. Colchicine inhibits microtubule development at low concentrations but stimulates microtubule depolymerization at higher concentrations. At high doses, it causes significant damage to normal tissues, limiting its utility in cancer therapy [
76]. Colchicine is an anti-inflammatory substance extracted from the leaves, flowers and seeds of saffron and has long been included in the prescription drug for cancer patients, but the same problem has always arisen: the drug attacks both cancer and healthy cells, destroying them [
147]. In a recent study, the stabilization of colchicine was done by attaching a chain of amino acids that make it inert, and the colchicine molecule moves freely through the body in this state, without affecting the healthy cells it encounters. Once in contact with the tumor, the amino acid chain is removed by an enzyme present on the surface of the cancer, called MMP-1. Thus, Colchicine is activated and destroys the surrounding cancer cells. MMP-1 (matrix metalloproteinases) is an enzyme that plays a vital role in destroying the extracellular matrix. Tumours use it to grow and invade healthy tissue [
148]. The enzyme increases blood flow around it, building new blood vessels and giving the tumor access to nutrients and oxygen. By destroying it, the resources needed for tumor growth and metastasis are cut off. The results of the study showed that the use of the enzyme MMP-1 as an activating agent helps the drug treat secondary tumors caused by cancer after it has spread in the body [
148].
Vinblastine sulfate, USP is the salt of an alkaloid obtained from Vinca rosea Linn, the flowers of a common medicinal plant (known as
Catharanthus roseus G Don). Before the design and development of this drug, the generic name was vincaleucoblastin, abbreviated VLB. It is a statokinetic oncolytic agent. In vitro treatment with this preparation stops the growth of cells at the metaphase level. Chemical and physical evidence indicates the empirical formula of vinblastine as C46H58N4O9H2SO4 and that it is a dimeric alkaloid containing both indole and dihydroindole in equal parts [
149].
Vincristine is available as a lyophilisate for the preparation of a solution for intravenous administration [
150]. However, the reduced bioavailability and dose-dependent neurotoxicity limit the therapeutic utility of this agent. As a result, incorporation into target transport pharmaceutical forms such as liposomes has been an important prospect. Injections with liposomes with vincristine sulfate, 0.16 mg/mL (Marqibo
®) is a new formulation in which Vincristine is encapsulated in sphingomyelin and cholesterol nanoparticles, to increase the release and intensification of the therapeutic dose of Vincristine [
150,
151].
Vindesine is marketed as vindesine sulfate and approved by the FDA in 1994. The mode of action of vindesine sulfate is not completely known [
152]. Like other Vinca alkaloids, vinblastine sulfate and vincristine sulfate, vindesine sulfate block cells in metaphase during mitosis [
90]. In vitro investigation has also shown that vindesine sulfate prevents malignant cells from invading normal tissue However, comparative studies with these three alkaloids have shown significant differences between their molecular effects. Vindesine sulfate is 3 times more potent than vincristine and almost 10 times more potent than vinblastine in blocking the effect of mitosis in tissue culture studies designed to block 10% to 15% of cells in mitosis [
108]. At dose concentrations that block 40–50% of the cells in mitosis vindesine sulfate and vincristine are approximate equal potency and both have 3 times the potency of vinblastine. Also, qualitative differences were observed between the three alkaloids [
108]. At low doses, vinblastine produces a predominance of cells in the post-metaphase, in which the center and chromosomes appear very obvious. Cells exposed to vincristine show spherical metaphase with compact chromosomes on a contracted spindle. Unlike vinblastine, vindesine sulfate produces few post-metaphase cells [
153]. In cells exposed to vindesine sulfate, the spindles were inflated with scattered chromosomes, in stark contrast to the tightly-packed chromosomes observed with vincristine. Vindesine sulphate showed oncolytic activity in patients with relapses during polychemotherapy treatment that included vincristine. In laboratory animals and humans, the biliary system is the major route of excretion of vindesine sulfate [
76].
Vinorelbine is another Vinca alkaloid that’s semi-synthetic and sold by the name Navelbine. It is a chemotherapeutic drug for treating non-small cell lung cancer that has spread metastatically (NSCLC) (
https://pubchem.ncbi.nlm.nih.gov/compound/Vinorelbine). It is administered by intravenous injection or by mouth during the first-line therapy of advanced or metastatic NSCLC in combination with other drugs (e.g., cisplatin). It has been licensed for therapeutic usage in the United States in 1994 [
154].
Overall conclusion
Alkaloids such as Colchicine from Colchicum autumnale; vinblastine, vincristine, vindesine, and vinorelbine (Vinca alkaloids) from Catharanthus roseus; and Vincamine from Vinca minor are promising anticancer properties. These alkaloids through their binding to microtubulins, one of the key components of the cytoskeleton, form the tubulin-alkaloid complex. These complexes thereof inhibit cancer cell migration and metastatic potential of the cell resulting in Programmed Cell Death and apoptosis of cancer cells. These alkaloids can be used in combination with chemotherapy regimens, as they do not impart cross-resistance to commonly used DNA alkylating drugs. However, a strong spectrum of biotechnological studies on in vitro production of these compounds is required, to which plant callus suspension cultures with different biotic and abiotic elicitors in bioreactors may have the potential to be new frontiers for the production of compounds with anticancer activity. For primary and secondary chemoprevention as well as cancer management as a whole, a comprehensive research program is warranted for the discovery of new alkaloids along with their metabolic effects and molecular actions such as vinca alkaloids, to develop novel anticancer drugs followed by clinically relevant recommendations for dose and efficacy, which is often underrepresented.
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