Mensacarcin is a highly oxygenated

polyketide In organic chemistry, polyketides are a class of natural products derived from a Precursor (chemistry), precursor molecule consisting of a Polymer backbone, chain of alternating ketone (, or Carbonyl reduction, its reduced forms) and Methylene gro ...

first isolated from soil-dwelling ''

Streptomyces bottropensis ''Streptomyces bottropensis'' is a bacterium species from the genus ''Streptomyces'' which has been isolated from soil.Deutsche Sammlung von Mikroorganismen und Zellkulturenbr>/ref> ''Streptomyces bottropensis'' produces bottromycin, dunaimycin ...

'' bacteria. The molecule is a

secondary metabolite Secondary metabolites, also called ''specialised metabolites'', ''secondary products'', or ''natural products'', are organic compounds produced by any lifeform, e.g. bacteria, archaea, fungi, animals, or plants, which are not directly involved ...

, and can be obtained in large amounts from its producing organism. Due to its unique properties it is an important model for drug development against

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

and other

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

Medical properties

NCI-60 The NCI-60 cancer cell line panel is a group of 60 human cancer cell lines used by the National Cancer Institute (NCI) for the screening of compounds to detect potential anticancer activity. Purpose The screening procedure is called the NCI- ...

anti-cancer compound screening mensacarcin has a high

cytostatic 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 and induce cell death. Cytostasis is an important prerequisite ...

effect against almost all cell lines (mean of 50% growth inhibition) and a relatively selective

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...

effect against melanoma cells. Low

COMPARE Comparison or comparing is the act of evaluating two or more things by determining the relevant, comparable characteristics of each thing, and then determining which characteristics of each are similar to the other, which are different, and t ...

correlation with standard antitumor agents indicate a unique mechanism of action. Further examinations reveal mensacarcin effecting the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

Potential use in cancer therapy

With its unique mechanism, effective also in BRAF

V600E V600E is a mutation of the '' BRAF'' gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600. It is a driver mutation in a proportion of certain diagnoses, including melanoma, hairy cell leukemia, papillary thyroid carcinoma ...

mutation

cell line An immortalised cell line is a population of cells from a multicellular organism that would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cells ...

s, mensacarcin is a promising model for the development of new anticancer drugs. Existing therapies for melanoma are limited. Mensacarcin's powerful effect against melanoma cells make it especially valuable for this disease.

Mechanism of action

Specific disruption of mitochondrial function

Mitochondria provide most of the energy used by

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

cells. In a study at the Oregon State University a synthesized

fluorescent Fluorescence is one of two kinds of photoluminescence, the emission of light by a substance that has absorbed light or other electromagnetic radiation. When exposed to ultraviolet radiation, many substances will glow (fluoresce) with color ...

probe of mensacarcin was localized to the mitochondria within 20 minutes of treatment. Live-cell bioenergetic

flux analysis Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications in physics. For transport phenom ...

showed rapid disturbance of energy production and of mitochondrial function. The localization together with the metabolic effects provide evidence that mensacarcin targets mitochondria.

Induction of cell death

Mitochondria are also important in

cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...

signaling. Mensacarcin in melanoma cells activates

apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...

pathways related to

caspase 3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are als ...

and

caspase 7 Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the ''CASP7'' gene. ''CASP7'' orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs ...

, and thus induces cell death. After mensacarcin treatment of two melanoma cell lines, the cells showed characteristic

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

condensation Condensation is the change of the state of matter from the gas phase into the liquid phase, and is the reverse of vaporization. The word most often refers to the water cycle. It can also be defined as the change in the state of water vapor ...

as well as distinct poly(ADP-ribose)polymerase-1 cleavage;

flow cytometry Flow cytometry (FC) is a technique used to detect and measure the physical and chemical characteristics of a population of cells or particles. In this process, a sample containing cells or particles is suspended in a fluid and injected into the ...

identified a large population of apoptotic cells; single-cell

electrophoresis Electrophoresis is the motion of charged dispersed particles or dissolved charged molecules relative to a fluid under the influence of a spatially uniform electric field. As a rule, these are zwitterions with a positive or negative net ch ...

indicated that mensacarcin causes

genetic instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or an ...

, a sign of early apoptosis.

Effect in melanoma cell lines with BRAF V600E mutation

The BRAF V600E mutation is associated with drug resistance. Due to its independent mechanism, mensacarcin has an undiminished effect in melanoma cell lines with this mutation (NCI 60 cell lines SK-Mel-28 and SK-Mel-5).

References

{{reflist Polyketides Oncology Cancer research Cancer Melanoma