Plant alkaloids and terpenoids in chemotherapy

ATC CODE: 101C

DEFINITION: Alkaloids and terpenoids are compounds derived from plants. Some have anticancer activity and have been developed into useful chemotherapeutic agents. Subclasses of this group include vinca alkaloids, taxanes, podophyllotoxins, epipodophyllotoxins, camptothecins, ellipticine, and colchicine.

Cancers treated or prevented: Breast cancer, ovarian cancer, lung cancer, prostate cancer, myelomas, lymphomas, leukemias

Delivery routes: Intravenous

How these drugs work: Plants are an important source of natural products that are effective in treating human cancer, with several useful chemotherapeutic agents currently on the market or in clinical trials. Specifically, many plant-derived alkaloids and terpenoids have significant anticancer properties. Synthetic and semi-synthetic derivatives of alkaloid and terpenoid compounds with anticancer activity have also been developed. In plants, these compounds are produced as secondary metabolites, defense chemicals that inhibit cell division in invading pathogens. These same cytostatic compounds can be helpful in cancer treatment by stopping the growth of cancer cells. Some examples of alkaloids and terpenoids used in chemotherapy are vinca alkaloids, podophyllotoxins, and taxanes.

Alkaloids are naturally occurring amines produced by plants and are grouped into several classifications, usually based on the metabolic pathway through which they are generated. These classifications include indoles, purine, pyridine, and isoquinoline, with terpenoids one classification of alkaloids. Terpenoids are sometimes referred to as isoprenoids and are classified according to the number of isoprene units they contain. For example, monoterpenoids comprise two isoprene units, whereas diterpenoids are composed of four isoprene units.

Four structural classes of plant-derived anticancer agents of alkaloid or terpenoid origin are available in the United States—vinca alkaloids, taxanes, podophyllotoxins, and camptothecins. These compounds affect cell division and deoxyribonucleic acid (DNA) synthesis or function.

The search for anticancer agents from plants was initiated in 1947 when podophyllotoxins from the American mayapple (Podophyllum peltatum) inhibited the growth of tumor cells in laboratory experiments. The subsequent discovery of antileukemic properties of vinblastine and vincristine, bis-indole alkaloids derived from the Madagascar periwinkle (Catharanthus roseus), spurred broad investigations of plant-derived compounds for possible anticancer activity. C. roseus was found to be a storehouse of more than seventy-five alkaloids, several of which possess anticancer activity. Among other plant species that have provided clinically useful drugs are Taxus brevifolis, the source of diterpene taxol; Ochrosia elliptica, one of the sources of the pyridocarbazole alkaloid ellipticine; and Camptotheca acuminata, which contains camptothecin.

The leaves of C. roseus, formerly Vinca roseus, contained cytotoxic compounds. Among these compounds were two terpenoid indole alkaloids, vinblastine and vincristine, which subsequently became the first natural anticancer agents used clinically. Vinblastine and vincristine, together with several semisynthetic derivatives, are termed vinca alkaloids. Although they have been in clinical usage since the 1970s, the vinca alkaloids are still beneficial chemotherapeutic agents with well-known antimitotic activity. Vinca alkaloids bind specific sites on tubulin and prevent tubulin assembly into microtubules, which are essential for cell division.

Soon after the introduction of vinblastine and vincristine, intensive chemical research was undertaken to develop semisynthetic derivatives with higher activity, lower toxicity, and broader anticancer effects. Several successful semisynthetic derivatives were developed, including vindesine, vinorelbine, and vinflunine. Vindesine has a vincristine-like spectrum of activity and is used mainly to treat melanoma, acute lymphoblastic leukemia, and advanced non-small-cell lung cancer. Vinorelbine has reduced side effects and treats non-small-cell lung and breast cancer, with utility toward other cancers, including lymphoma and esophageal and prostate cancers, under clinical investigation. Vinflunine is a semisynthetic fluorinated derivative of vindesine used against advanced cancers of the bladder, urethra, ureter, and kidney and is being studied against other forms.

Another class of plant alkaloids used in chemotherapy is the taxanes. Taxanes are derived from either the bark or needles of some species of yew tree. Taxanes used as chemotherapeutic agents include paclitaxel and docetaxel. Paclitaxel was originally derived from the bark of the Pacific yew tree and is one of the most effective plant-derived chemotherapeutic agents. Patients with refractory ovarian cancer, metastatic breast cancer, advanced lung cancer, cancers of the head and neck, melanoma, and lymphomas often respond positively to treatment with paclitaxel. The taxanes disrupt the function of microtubules, inhibiting cell division by preventing the separation of chromosomes during anaphase.

Other classes of plant alkaloids used in chemotherapy include podophyllotoxins, camptothecins, ellipticines, and colchicine. Podophyllotoxins, or epipodophyllotoxins, are alkaloids naturally occurring in the root of the American mayapple or mandrake (Podophyllum emodi). A rare Himalayan mayapple (Podophyllum hexandrum) has also been found to contain active compounds. Efforts to obtain these compounds through recombinant technologies are underway. Some epipodophyllotoxin derivatives, etoposide and teniposide, are used in cancer treatment. Semisynthetic derivatives such as amsacrine and etoposide phosphate also exist. Podophyllotoxins and their derivatives prevent cell division in tumor cells by keeping them from entering the cell cycle and undergoing DNA replication.

Camptothecin is a quinoline alkaloid isolated from C. acuminata. Examples of camptothecins used in chemotherapy include topotecan, irinotecan, and 9-Aminocamptothecin (9-Amino-CPT). Topotecan is used to treat ovarian cancer, and irinotecan is marketed for the treatment of metastatic cancer of the colon or rectum. Ellipticine is an alkaloid isolated from an evergreen tree of the Apocyanaceae family. Ellipiticine and its derivatives, including elliptinium, are highly effective against several types of cancer, with limited side effects. Colchicine is a tricyclic tropane alkaloid from the autumn crocus (Colchicum autumnale) and gloriosa lily (Gloriosa superba). Colchicine has been used effectively to treat chronic myelocytic leukemia, but toxic or near-toxic doses are required for therapeutic benefit. For this reason, colchicine and its analogs are primarily used as tools to study new mitotic inhibitors rather than in chemotherapy.

Podophyllotoxins, camptothecins, ellipticines, and their derivatives function as either type I or type II topoisomerase inhibitors, enzymes essential for critical steps in cell division, DNA transcription, and replication. Colchicines prevent tubulin polymerization during the cell cycle.

Side effects: Side effects of plant alkaloids and terpenoids used in chemotherapy include lowered resistance to infection, bruising or bleeding, anemia, constipation, cramps, diarrhea, nausea, peripheral neuropathy (numbness or tingling in hands or feet), headaches, tiredness, and hair loss. Mouth sores and ulcers, changes in taste, and loss of appetite can also occur. Skin rashes and allergic reactions are seen less commonly.

Bibliography

Barreto, George E., and Amirhossein Sahebkar. Pharmacological Properties of Plant-Derived Natural Products and Implications for Human Health. Springer, 2021. 

Boța, Mihaela, et al. "Exploring Synergistic Interactions between Natural Compounds and Conventional Chemotherapeutic Drugs in Preclinical Models of Lung Cancer." Pharmaceuticals, vol. 17, no. 5, 2024, p. 598. doi.org/10.3390/ph17050598.

Haridas, Madhathilkovilakathu. Drugs from Nature: Targets, Assay Systems and Leads. Springer, 2024.

Huang, Wenqian, et al. "Biosynthesis Investigations of Terpenoid, Alkaloid, and Flavonoid Antimicrobial Agents Derived from Medicinal Plants" Antibiotics, vol. 11, no. 10, 2022. doi.org/10.3390/antibiotics11101380.

Koehn, Frank E. Natural Products and Cancer Drug Discovery. Humana, 2013.

Perry, Michael C., ed. The Chemotherapy Source Book. 5th ed. Lippincott, 2012.

Sousa-Pimenta, Mário, et al. "Chemotherapeutic Properties and Side-effects Associated with the Clinical Practice of Terpene Alkaloids: Paclitaxel, Docetaxel, and Cabazitaxel." Frontiers in Pharmacology, vol. 14, 2023. doi.org/10.3389/fphar.2023.1157306.

Ul-Islam, Shahid, and Javid Ahmad Banday. Chemistry of Biologically Potent Natural Products and Synthetic Compounds. Wiley-Scrivener, 2021.