Pharmacology of natural compounds found in clinical trials used for ameliorating/preventing Cancer
Priyanka Kumari1, Arjun Singh2*
1Department of Pharmacognosy, School of Pharmaceutical Sciences,
Bhagwant University, Sikar Road, Ajmer, Rajasthan 305004, India.
2Department of Medicine, Sidney Kimmel Medical College,
Thomas Jefferson University, Philadelphia, PA 19107, United States.
*Corresponding Author E-mail: arjunphar@gmail.com
ABSTRACT:
In the field of oncology, the use of herbal medicines as a supplemental or alternative treatment option has been generally accepted (Catharanthus roseus, Podophyllum peltatum L., Taxus brevifolia Nutt., Taxus baccata, etc.). As a result, several brand-new cytotoxic chemicals are discovered each year in plants, opening up fresh avenues for the treatment of cancer. The examination of naturally occurring molecular entities that could benefit the pharmaceutical business is a focus of many researchers. The search for clinical efficacy validation follows the discovery of drugs with anticancer activity in preclinical trials. Only 29 of the 240 anticancer medicines licensed in the previous 40 years are entirely synthetic, which could be attributed to the advantages of natural substances such as lower side effects and the ability to affect numerous Signaling pathways involved in the carcinogenesis process. In addition, synthetic compounds with natural pharmacophores that imitate the effects of natural products have been licensed as anticancer medications throughout the past ten years. Since the start of cancer research, phytochemicals have been a focal point because they were some of the first antineoplastic medicines found (e.g., leucovorin in 1950, carzinophilin in 1954, vincristine in 1963, actinomycin D in 1964, etc.). Additionally, their research is still ongoing today. It is crucial to note that natural substances are used both as adjuvants and chemotherapeutic agents in the treatment of cancer. By summarizing the three aspects of natural chemicals' anticancer action, this review offers a fresh viewpoint on their use in the field of oncology. Chemotherapeutic drugs because of their inherent antitumor effects, chemopreventive drugs, and sensitizers for multi-drug resistance are the first three categories.
KEYWORDS: Cancer, Oncology, natural products, Clinical trial, herbal medicine.
INTRODUCTION:
A library of prospective therapeutic agents is provided by terrestrial plants, microorganisms, slime molds, and the marine environment, which all serve as significant sources of novel pharmacologically active compounds1. Many popular medications that have been or are still being used in clinical settings are either directly or indirectly derived from natural materials2. The secondary metabolites of plants continue to be important for drug design despite the rise in popularity of synthetic products that made it possible for many drugs to exist today, as their fundamental structural elements act as models for the synthesis or semi-synthesis of novel compounds for the treatment of human diseases3.The naturally occurring molecules continue to play a dominating role in the treatment of human illnesses despite the safety-efficacy report of synthesized medications being disputed due to their high patient tolerance and acceptance4. When compared to phytocompounds, which have been shown to be less toxic and more effective, conventional chemotherapy drugs (such as methotrexate and cisplatin) are associated with severe adverse reactions like hair loss, gastrointestinal lesions, bone marrow suppression, neurologic dysfunction, and drug resistance5-8. Most notably in the field of antibiotics and cancer treatments, chemicals found in nature currently make up a significant fraction of modern pharmacological agents, of which 60 to 80% are derived from natural compounds.Additionally, roughly a third of the top-selling medications in the world are made of natural substances or their derivatives. The most famous instance of this is when Alexander Fleming famously noticed that "around a large colony of a contaminating mold the staphylococcus colonies became transparent and were obviously undergoing lysis". This led him to the legendary discovery of the first antibiotic penicillin from the fungus Penicillium notatum. Even in the realm of cancer treatment, antibiotics stood out as one of the most significant chemotherapeutic drugs. Actinomycin, ansamycin, anthracycline, bleomycin, epothilone, and staurosporine are a few examples. Breast cancer and lymphoma are just two of the many cancer forms that are treated with anthracycline chemotherapy regimens9.
The four most prevalent anthracyclines are doxorubicin (derived from bacteria), daunorubicin, epirubicin, and idarubicin, the first two of which were the first to be used in therapeutic settings10. Multiple molecular mechanisms, including topoisomerase II, DNA, and RNA inhibitions, are responsible for their cytotoxic effects. By severing DNA double strands when the cell is replicating, topoisomerase II lessens DNA supercoiling. Anthracyclines generate a ternary complex with DNA and the isoenzyme topoisomerase II that splits double-stranded DNA. The most common isoenzyme is topoisomerase II (TopII), which is substantially abundant in cancerous cells11.Anthracyclines disrupt TopII's enzymatic activity when attached to it, stabilize DNA breaks, and prevent DNA replication. Additionally, anthracyclines generate adducts when they intercalate with DNA bases and impede the activity of DNA and RNA polymerases, which prevents the synthesis of DNA and RNA. Anthracycline interactions with nucleic acids, particularly DNA, have been well studied since the 1990s. By producing 3D crystallographic structures of DNA-anthracycline complexes, the substantial research done allowed for the observation of binding patterns and base pair interaction behavior between DNA strands and anthracyclines. These structures depict how anthracyclines interact with DNA base pairs to affect their mobility and demonstrate how these compounds are tightly linked to DNA base pairs through many hydrogen bonds12-15.
However, despite the excellent tumor regression results, anthracycline therapy carries a considerable risk for cardiac problems. The glycopeptide antibiotic family includes bleomycin, which has its main use as an antineoplastic drug16-18. Through the binding of metal ions, which causes the creation of metallobleomycin complexes, it causes oxidative damage to DNA. Additionally, after exposure to this antibiotic, chromosomal abnormalities, chromatid breaks, and translocations were noted. For the treatment of a number of cancers, including squamous cell carcinomas, testicular cancers, Hodgkin and non-Hodgkin lymphomas, bleomycin has FDA approval19.
METHODS:
Materials
Numerous active agents are undergoing preclinical and clinical studies right now.It is crucial to emphasize the noteworthy accomplishments made in this field of study, with some secondary plant metabolites already being used in therapeutic settings and others being investigated for use as anticancer medicines in ongoing clinical studies20.Resveratrol is a phytoalexin and stilbenoid produced by various plants, including grapes, peanuts, cranberries, and blueberries. It has been extensively explored for its potential to treat cancer21. Red wine also contains sizable quantities of resveratrol.Resveratrol's ability to inhibit tumor growth has been linked to a number of previously identified mechanisms, including I an anti-inflammatory effect by reducing the expression of transcription factors (NF-κB) and mediators of inflammation (prostaglandin E2); (ii) a proapoptotic effect by interfering with multiple Signaling pathways; and (iii) an antioxidant effect that manifested in vivo through gene regulation and was partially mediated.The primary ingredients in turmeric are called curcuminoids, and curcumin is a diarylheptanoid. (Curcuma longa)22. As a result of its capacity to inhibit the activity of NF-κB and COX-2 while reducing the formation of prostaglandins, it has historically been utilized as an anti-inflammatory substance. As shown in Table, the antitumoral properties of curcumin are mediated through inhibition of many Signaling pathways involved in the control of proliferation, apoptosis, survival, angiogenesis, and metastasis. A recent study revealed that curcumin targets dual-specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome23. This information is relevant to the ongoing search for potential targets of curcumin that may be related to its antitumoral activities24.
Major phytochemicals used for Cancer clinical trails
Table 3. Relevant examples of natural compounds found in clinical trials25-39
|
Natural Compound |
Identifier/Status |
Cancer Type/ Conditions |
Title |
Observations |
|
Resveratrol |
NCT00256334/ Completed |
Colon cancer |
Resveratrol for Patients With Colon Cancer |
Patients were randomly assigned to one of four dose cohorts: plant-derived resveratrol tablets (80 mg/day and 20 mg/day), Grape Powder dissolved in water and taken orally (120 g/day and 80 g/day). |
|
NCT02261844/ Withdrawn (No funding) |
Liver cancer |
Resveratrol and Human Hepatocyte Function in Cancer |
Resveratrol 1 g daily for 10 days |
|
|
NCT01476592/ Completed |
Neuroendocrine tumor |
A Biological Study of Resveratrol’s Effects on Notch-1 Signaling in Subjects With Low Grade Gastrointestinal Tumors |
5 g/day of resveratrol orally, in two divided doses of 2.5 g each without a break in therapy for a total of three cycles |
|
|
NCT00433576/ Completed |
Colorectal cancer |
Resveratrol in Treating Patients With Colorectal Cancer That Can Be Removed By Surgery |
STAGE II: Patients receive oral resveratrol on days 1–8 and undergo colorectomy on day 9. |
|
|
NCT00098969/ Completed |
Unspecified Adult Solid Tumor, Protocol Specific |
UMCC 2003-064 Resveratrol in Preventing Cancer in Healthy Participants |
This phase I trial is studying the side effects and best dose of resveratrol in preventing cancer in healthy participants. |
|
|
NCT03253913/ Unknown |
Lymphangioleiomyomatosis |
Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial |
Resveratrol 250 mg daily for the first 8 weeks, followed by 250 mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks. |
|
|
NCT04266353/ Suspended (Due to COVID-19) |
Breast cancer |
Effect of Resveratrol on Serum IGF2 Among African American Women |
Participants with receive resveratrol at 150 mg daily for 6 weeks |
|
|
NCT00578396/ Unknown |
Colon cancer |
Phase I Biomarker Study of Dietary Grape-Derived Low Dose Resveratrol for Colon Cancer Prevention |
- |
|
|
Curcumin |
NCT03980509/ Recruiting |
Breast Cancer |
A "Window Trial" on Curcumin, the Active Compound in Turmeric, for Invasive Breast Cancer Primary Tumors |
Curcumin (500 mg) will be orally administered twice a day, after each meal from the time surgical resection is scheduled until the night before surgical resection. |
|
NCT04294836/ Not yet Recruiting |
Cervical Cancer |
Randomized Phase II Clinical Trial of Oral Turmeric Supplementation in Patients With Advanced Cervical Cancer |
Curcumin administered in a dosage of 2000 mg daily, in association with cisplatin and radiotherapy for 16 weeks |
|
|
NCT02724202/ Active, not recruiting |
Colon Cancer |
A Pilot, Feasibility Study of Curcumin in Combination With 5FU for Patients With 5FU-Resistant Metastatic Colon Cancer |
Curcumin at a dosage of 500 mg twice/day will be orally administered for 2 weeks. Patients will continue on curcumin at the same dose for an additional 6 weeks while being treated with 3 cycles of 5-fluorouracil |
|
|
EGCG |
NCT02891538/ Recruiting |
Colorectal Cancer |
A Pilot Study to Evaluate the Chemopreventive Effects of Epigallocatechin Gallate (EGCG) in Colorectal Cancer (CRC) Patients With Curative Resections |
EGCG (highly purified and refined green tea extract-Teavigo™) administered at a dosage of 450 mg twice a day |
|
NCT01317953/ Available |
Lung Cancer |
Phase I Study of Oral Green Tea Extract as Maintenance Therapy for Extensive-stage Small Cell Lung Cancer |
Increasing doses of EGCG (400, 800, 1200, 1600 and 2000 mg) administered daily |
|
|
NCT00917735/ Completed |
Breast Cancer |
Phase II, Randomized, Double-blind, Placebo-controlled, Study of the Efficacy of Green Tea Extract on Biomarkers of Breast Cancer Risk in High Risk Women With Differing Catechol-O-methyl Transferase (COMT) Genotypes |
Oral administration of two Green tea extract capsules containing 51.7% EGCG, twice daily after breakfast and dinner for one year. |
|
|
Quercetin |
NCT01538316/ |
Prostate Cancer |
Clinical Trial on the Effectiveness of the Flavonoids Genistein and Quercetin in Men With Rising Prostate-specific Antigen |
500 mg of quercetin supplement (+ vitamin C + folic acid + vitamin B3) administered daily over a period of six months, followed by genistein and placebo administration. |
|
NCT03476330/ Recruiting |
Squamous Cell Carcinoma |
Quercetin Chemoprevention for Squamous Cell Carcinoma in Patients With Fanconi Anemia |
Quercetin administered orally twice daily at an wheight-based adjusted dosage (maximum 4000 mg/day). |
|
|
Betulinic acid |
NCT00346502/ Suspended |
Dysplastic Nevus Syndrome |
Phase I/II Evaluation of Topical Application of 20% Betulinic Acid Ointment in the Treatment of Dysplastic Nevi With Moderate to Severe Dysplasia |
Daily application of the 20% betulinic acid ointment to the dysplastic nevi site for a period of four weeks. |
|
Artemisimin |
NCT00764036/ Completed |
Breast Cancer |
Prospective Open Uncontrolled Phase I Study of Compatibility, Safety&Pharmacokinetics of Artesunate, a Semisynthetic Derivative of Artemisinin From the Chinese Herb Artemisia Annua in Patients With Metastatic/Locally Advanced Breast Cancer |
The administration of the drug was as follows: daily single oral doses of 100, 150 or 200 mg of artesunate, for 4 weeks. |
|
NCT03093129/ Recruiting |
Colorectal Cancer |
Phase II Randomised, Double Blind, Placebo Controlled Trial of Neoadjuvant Artesunate in Stage II/III Colorectal Cancer in Vietnamese Patients |
Daily administration of artesunate (200 mg) for 14 days. |
|
|
NCT04098744/ Recruiting |
Cervical Neoplasia |
A Phase II Double Blind, Placebo-controlled, Randomized Trial of Artesunate Vaginal Inserts for the Treatment of Patients With Cervical Intraepithelial Neoplasia (CIN2/3) |
Participants will receive three 5-day cycles of artesunate inserts, 200 mg per day, at weeks 0, 2, and 4. |
|
|
Rutin |
NCT00003365/ Terminated |
Colon Cancer |
The Effect of Plant Phenolic Compounds on Human Colon Epithelial Cells |
The administration of rutin was twice a day, for 6–10 weeks. Other phytocompounds (e.g. curcumin, quercetin) were evaluated in this study as well. |
|
Ginseng |
NCT00631852/ Completed |
Breast Cancer |
A Phase II Biomarker Trial of Gelatin Encapsulated Extract of American Ginseng Root (LEAG) in Breast Cancer |
The administration of American Ginseng Root extract was organised as follows: four 250 mg tablets daily for 5–14 days prior to surgery. |
|
NCT02603016/ Completed |
Lung Neoplasm Breast Carcinoma |
Phase 1 Study of Clinical Nutrition That Research Safty and Efficacy in Lung Neoplasms And Breast Carcinoma |
Two tablets of Ginseng were administered by mouth, twice a day for 42 days. |
CONCLUSION:
The findings of this systematic review indicate that using, Time and numerous resources are needed for the process of moving from in vitro to in vivo testing and for accessing clinical trials. Using methods created by the Organization for Economic Co-operation and Development (OECD) and the correlation of high-speed screening, biological phenotyping, and integration with computer modeling in a new approach to the toxicological system, the time needed for toxicological testing, a crucial step, has been decreased as a result of technological advancements. Clinical trials are implemented based on the attainment of the dose with a therapeutic impact of the dose because in vitro studies require less complicated procedures than in vivo studies. Unfortunately, access to a molecule during the clinical trial phase depends primarily on financial factors at this time, with the majority of studies being halted owing to a lack of funding. Additionally, few isolated natural compounds are actually converted into clinically useful medications and promising preclinical results frequently do not translate to success in clinical trials40-43.
CONFLICT OF INTEREST:
The author has no conflicts of interest.
ACKNOWLEDGMENTS:
The author would like to thank NCBI, PubMed and Web of Science for the free database services for their kind support during this study.
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Received on 24.12.2022 Modified on 27.04.2023
Accepted on 31.07.2023 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Ana. 2024; 14(3):195-200.
DOI: 10.52711/2231-5675.2024.00035