Betulinic acid is a naturally occurring pentacyclic

triterpenoid Triterpenes are a class of chemical compounds composed of three terpene units with the molecular formula C30H48; they may also be thought of as consisting of six isoprene units. Animals, plants and fungi all produce triterpenes, including squal ...

which has antiretroviral, anti

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

l, and

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase. It is found in the bark of several species of plants, principally the

white birch ''Betula papyrifera'' (paper birch, also known as (American) white birch and canoe birch) is a short-lived species of birch native to northern North America. Paper birch is named for the tree's thin white bark, which often peels in paper like ...

(''Betula pubescens'') from which it gets its name, but also the ber tree (''

Ziziphus mauritiana ''Ziziphus mauritiana'', also known as Indian jujube, Indian plum, Chinese date, Chinese apple, ber, and dunks is a tropical fruit tree species belonging to the family Rhamnaceae. It is often confused with the closely related Chinese jujube ( ...

''), selfheal (''

Prunella vulgaris ''Prunella vulgaris'', the common self-heal, heal-all, woundwort, heart-of-the-earth, carpenter's herb, brownwort or blue curls, is a herbaceous plant in the mint family Lamiaceae. Self-heal is edible: the young leaves and stems can be eaten raw ...

''), the

tropical The tropics are the regions of Earth surrounding the Equator. They are defined in latitude by the Tropic of Cancer in the Northern Hemisphere at N and the Tropic of Capricorn in the Southern Hemisphere at S. The tropics are also referred to ...

carnivorous plants Carnivorous plants are plants that derive some or most of their nutrients from trapping and consuming animals or protozoans, typically insects and other arthropods. Carnivorous plants still generate some of their energy from photosynthesis ...

'' Triphyophyllum peltatum'' and ''

Ancistrocladus heyneanus ''Ancistrocladus heyneanus'' or Kardal is a liana endemic to the Western Ghats of southwestern India India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second- ...

'', '' Diospyros leucomelas'', a member of the

persimmon The persimmon is the edible fruit of a number of species of trees in the genus '' Diospyros''. The most widely cultivated of these is the Oriental persimmon, ''Diospyros kaki'' ''Diospyros'' is in the family Ebenaceae, and a number of non-per ...

family, '' Tetracera boiviniana'', the jambul (''

Syzygium ''Syzygium'' () is a genus of flowering plants that belongs to the myrtle family, Myrtaceae. The genus comprises about 1200 species, and has a native range that extends from Africa and Madagascar through southern Asia east through the Pacific. ...

formosanum''), flowering quince (''

Pseudocydonia sinensis ''Pseudocydonia sinensis'' or Chinese quince () is a deciduous or semi-evergreen tree in the family Rosaceae, native to southern and eastern China. It is the sole species in the genus ''Pseudocydonia''. Its hard, astringent fruit is used in tra ...

'', former ''Chaenomeles sinensis KOEHNE''), (''Chaenomeles sinensis KOEHNE'' is now named ''

'')

rosemary ''Salvia rosmarinus'' (), commonly known as rosemary, is a shrub with fragrant, evergreen, needle-like leaves and white, pink, purple, or blue flowers, native to the Mediterranean region. Until 2017, it was known by the scientific name ''Rosmar ...

, and ''

Pulsatilla The genus ''Pulsatilla'' contains about 40 species of herbaceous perennial plants native to meadows and prairies of North America, Europe, and Asia. Derived from the Hebrew word for Passover, "pasakh", the common name pasque flower refers to the ...

chinensis''.

Antitumor activity

In 1995, betulinic acid was reported as a selective inhibitor of human melanoma. Then it was demonstrated to induce apoptosis in human neuroblastoma ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' in model systems. At one time, it was undergoing

drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...

with assistance from the Rapid Access to Intervention Development program of the

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...

. Also, betulinic acid was found active ''in vitro'' against neuroectodermal (

neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in th ...

medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...

Ewing's sarcoma Ewing sarcoma is a type of cancer that forms in bone or soft tissue. Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. The most common areas where it begins are the legs, pelvis, and chest wall. In about ...

) and malignant brain tumors,

ovarian carcinoma Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different cel ...

, in human

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

HL-60 cells, and malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines. In contrast, epithelial tumors, such as

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...

, colon, small cell lung and

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cance ...

s, as well as T-cell leukemia cells, were completely unresponsive to treatment with betulinic acid. The effects of betulinic acid as an anticancer agent in breast cancer is found to be

cannabinoid receptor Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recep ...

dependent. Betulinic acid behaves as a CB₁ antagonist and CB₂ agonist.

Mode of action

Regarding the mode of action of betulinic acid, little is known about its

antiproliferative Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division. Cytostasis is an important prerequisite for structured multic ...

and apoptosis-inducing mechanisms. In neuroectodermal tumor cells, betulinic acid–induced apoptosis is accompanied by caspase activation, mitochondrial membrane alterations and DNA fragmentation. Caspases are produced as inactive proenzymes, which are proteolytically processed to their active forms. These proteases can cooperate in proteolytic cascades, in which caspases activate themselves and each other. The initiation of the caspases cascade may lead to the activation of endonucleases such as caspase-activated DNAase (CAD). After activation, CAD contributes to DNA degradation. Betulinic acid induces apoptosis by direct effects on mitochondria, leading to cytochrome-C release, which in turn regulates the "downstream" caspase activation. Betulinic acid bypasses resistance to CD95 and

doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...

-mediated apoptosis, due to different molecular mechanism of betulinic acid-induced apoptosis. The role of

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

in betulinic acid-induced apoptosis is controversial. Fulda suggested a p53-independent mechanism of the apoptosis, based on no accumulation of wild-type p53 detected upon treatment with the betulinic acid, whereas wild-type p53 protein strongly increased after treatment with doxorubicin. The suggestion is supported by study of Raisova. Alternatively, Rieber suggested betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53. The study also demonstrated preferential apoptotic effect of betulinic acid on C8161 metastatic melanoma cells, with greater DNA fragmentation and growth arrest and earlier loss of viability than their nonmetastatic C8161/neo 6.3 counterpart. Comparing betulinic acid with other treatment modes, Zuco demonstrated it was less than 10% as potent as doxorubicin