HU-331
Encyclopedia
HU-331 is a quinone
anticarcinogenic drug synthesized from cannabidiol
, a cannabinoid in the Cannabis sativa
plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle
, cell apoptosis or caspase
activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible effect on the action of DNA topoisomerase I. The cannabinoid quinone HU-331 is a very specific inhibitor
of topoisomerase II, compared with most known anticancer quinones. One of the main objectives of these studies is the development of a new quinone
derived compound that produces anti-neoplastic activity while maintaining low toxicity at therapeutic doses.
, then inhibiting the catalytic activity of topoisomerase, which hinders the activity of these enzymes without introducing breaks into the DNA chains. HU-331 seems to be a catalytic inhibitor of topoisomerase II, probably by enzymatic ligation to the protein. This molecule does not cause damage to DNA, but protects cells from damage, natural, or induced by other inhibitors of topoisomerase II that act as inhibitors of topoisomerase. Even when 60% of the target cells are killed by treatment with HU-331, other cells' nucleic content remains unharmed, with less breakage of DNA chains that control important cellular functions.
Doxorubicin
, like other anticancer quinones, was used for chemotherapy
in human cancers for many years. The mechanism of action of these drugs has been the subject of considerable controversy since chemotherapeutic drugs exert their cytotoxic effect on target cells by nonspecific mechanisms. The doxorubicin damages DNA by intercalation
, the generation of reactive oxygen species
and inhibition of DNA topoisomerase I and II. This leads to breaking the chains of DNA single and double strands. The protein associated with these ruptures are the topoisomerase II and DNA damage is catalyzed by this enzyme. Thus, while doxorubicin and other anthraquinone
s act through many mechanisms such as apoptosis, abrogation
of the cell cycle cell, activation of caspases, generation of ROS
, inhibition of both topoisomerases, activation of intracellular
secondary messengers, etc.. Hu-331 is more active and less toxic, since it generates reactive oxygen species in the heart
and has a specific activity that gives great potential to develop as a new anticancer drug, according to Kogan et al.
Cannabinoids can act as anticancer compounds killing several oncogenic cells followed by direct interaction with cannabinoid receptors. The growth of glioma
is inhibited by a selective activation of the CB2 cannabinoid receptor and endogenous cannabinoids such as anandamide
inhibit the proliferation
of cells involved in lung cancer
. The reason behind the antitumor effect of HU-331 appears unknown as cannabinoid receptor antagonist
s do not inhibit HU-331, despite being mediated by a cannabinoid receptor. The HU-331 exerts an antiangiogenic effect accompanied by apoptosis of endothelial cells. Although in some studies. HU-331 has not caused the death of cells by oncogenic apoptosis. The conclusion that would lead cells to apoptosis which is based on treatment with the drug did not increase the proportion of cells containing DNA
Lues in the sub-G1 phase
and have not found the expression of caspase-3 in cancer cells.
Quinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
anticarcinogenic drug synthesized from cannabidiol
Cannabidiol
Cannabidiol is a cannabinoid found in Cannabis. It is a major constituent of the plant, representing up to 40% in its extracts.It has displayed sedative effects in animal tests...
, a cannabinoid in the Cannabis sativa
Cannabis sativa
Cannabis sativa is an annual herbaceous plant in the Cannabaceae family. Humans have cultivated this herb throughout recorded history as a source of industrial fibre, seed oil, food, recreation, spiritual enlightenment and medicine...
plant. It showed a great efficacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
, cell apoptosis or caspase
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible effect on the action of DNA topoisomerase I. The cannabinoid quinone HU-331 is a very specific inhibitor
Inhibitor
Something that restrains, blocks, or suppresses.Inhibitor or inhibition may refer to:* Corrosion inhibitor, a substance that decreases the rate of metal oxidation...
of topoisomerase II, compared with most known anticancer quinones. One of the main objectives of these studies is the development of a new quinone
Quinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
derived compound that produces anti-neoplastic activity while maintaining low toxicity at therapeutic doses.
Mechanism of action
Inhibitors of topoisomerases can act at two different levels. First inhibiting topoisomerase, which stabilize the topoisomerase-DNA complex and thus introduce DNA breaks in the wires that lead to apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, then inhibiting the catalytic activity of topoisomerase, which hinders the activity of these enzymes without introducing breaks into the DNA chains. HU-331 seems to be a catalytic inhibitor of topoisomerase II, probably by enzymatic ligation to the protein. This molecule does not cause damage to DNA, but protects cells from damage, natural, or induced by other inhibitors of topoisomerase II that act as inhibitors of topoisomerase. Even when 60% of the target cells are killed by treatment with HU-331, other cells' nucleic content remains unharmed, with less breakage of DNA chains that control important cellular functions.
Doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
, like other anticancer quinones, was used for chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
in human cancers for many years. The mechanism of action of these drugs has been the subject of considerable controversy since chemotherapeutic drugs exert their cytotoxic effect on target cells by nonspecific mechanisms. The doxorubicin damages DNA by intercalation
Intercalation
Intercalation is the insertion of a leap day, week or month into some calendar years to make the calendar follow the seasons or moon phases. Lunisolar calendars may require intercalations of both days and months.- Solar calendars :...
, the generation of reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
and inhibition of DNA topoisomerase I and II. This leads to breaking the chains of DNA single and double strands. The protein associated with these ruptures are the topoisomerase II and DNA damage is catalyzed by this enzyme. Thus, while doxorubicin and other anthraquinone
Anthraquinone
Anthraquinone, also called anthracenedione or dioxoanthracene is an aromatic organic compound with formula . Several isomers are possible, each of which can be viewed as a quinone derivative...
s act through many mechanisms such as apoptosis, abrogation
Abrogation
Abrogation may refer to:* Abrogation of Old Covenant laws, the ending or setting aside of the Old Testament ethics for the New Testament.* Denunciation of a treaty* Abrogation doctrine, a doctrine in United States constitutional law...
of the cell cycle cell, activation of caspases, generation of ROS
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
, inhibition of both topoisomerases, activation of intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
secondary messengers, etc.. Hu-331 is more active and less toxic, since it generates reactive oxygen species in the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and has a specific activity that gives great potential to develop as a new anticancer drug, according to Kogan et al.
Cannabinoids can act as anticancer compounds killing several oncogenic cells followed by direct interaction with cannabinoid receptors. The growth of glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
is inhibited by a selective activation of the CB2 cannabinoid receptor and endogenous cannabinoids such as anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
inhibit the proliferation
Proliferation
Proliferation may refer to:*Nuclear proliferation*Chemical weapon proliferation*Cell proliferation* The proliferative phase of wound healing...
of cells involved in lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
. The reason behind the antitumor effect of HU-331 appears unknown as cannabinoid receptor antagonist
Cannabinoid receptor antagonist
The discovery of the endogenous cannabinoid system led to the development of CB1 receptor antagonists. The first cannabinoid receptor "antagonist," rimonabant, was described in 1994. Rimonabant blocks the CB1 receptor selectively and it has been shown to decrease food intake and regulate...
s do not inhibit HU-331, despite being mediated by a cannabinoid receptor. The HU-331 exerts an antiangiogenic effect accompanied by apoptosis of endothelial cells. Although in some studies. HU-331 has not caused the death of cells by oncogenic apoptosis. The conclusion that would lead cells to apoptosis which is based on treatment with the drug did not increase the proportion of cells containing DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
Lues in the sub-G1 phase
G1 phase
The G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
and have not found the expression of caspase-3 in cancer cells.