A Washington State University research team has developed a drug delivery system using curcumin, the main ingredient in the spice turmeric, that successfully inhibits bone cancer cells while promoting growth of healthy bone cells.
The work could lead to better post-operative treatments for people with osteosarcoma, the second most prevalent cause of cancer death in children.
The researchers, including Susmita Bose, Herman and Brita Lindholm Endowed Chair Professor in the School of Mechanical and Materials Engineering, and graduate student Naboneeta Sarkar, report on their work in the journal, ACS Applied Materials and Interfaces.
Young patients with bone cancer are often treated with high doses of chemotherapy before and after surgery, many of which have harmful side effects.
Researchers would like to develop gentler treatment options, especially after surgery when patients are trying to recover from bone damage at the same time that they are taking harsh drugs to suppress tumor growth.
Turmeric has been used in cooking and as medicine for centuries in Asian countries, and its active ingredient, curcumin has been shown to have anti-oxidant, anti-inflammatory and bone-building capabilities.
It has also been shown to prevent various forms of cancers.
“I want people to know the beneficial effects of these natural compounds,” said Bose. “Natural biomolecules derived from these plant-based products are inexpensive and a safer alternative to synthetic drugs.”
However, when taken orally as medicine, the compound can’t be absorbed well in the body.
It is metabolized and eliminated too quickly.
In their study, the researchers used 3-D printing to build support scaffolds out of calcium phosphate.
While most implants are currently made of metal, such ceramic scaffolds, which are more like real bone, could someday be used as a graft material after bone cancer surgery.
The researchers incorporated curcumin, encapsulated in a vesicle of fat molecules into the scaffolds, allowing for the gradual release of the chemical.
The researchers found that their system inhibited the growth of osteosarcoma cells by 96 percent after 11 days as compared to untreated samples.
The system also promoted healthy bone cell growth.
“This study introduces a new era of integration – where modern 3D printing technology is coupled with the safe and effective use of alternative medicine, which may provide a better tool for bone tissue engineering,” said Bose.
The researchers are continuing the unique area of research, studying the benefits of integrating other natural compounds in biomedical technology.
Cancer is neither a single nor a modern disease.
In human, more than 200 different types of cancer are possible depending upon the types of tissue and/or cell.
The description of cancer was found in many ancient literatures including Egyptian “Edwin Smith” and “George Ebers” papyri, written between the 3000 BC2 and 1500 BC (Faguet, 2014).
The “Edwin Smith” papyrus refers to 8 cases of ulcers (tumors) of the breast that were removed by cauterization with a tool called “the fire drill.”
It describes the disease as: “there is no treatment” (Faguet, 2014).
A scientific look into the fossils of over 700 dinosaurs confirmed the existence of bone cancer.
Osteosarcoma (growths suggestive of the bone cancer) was also been noticed in the ancient human mummies in Egypt.
The word oncos (in Greek, it means swelling) was introduced by a Greek physician Galen (130–200 AD) to define tumors.
Successively the term oncology was developed.
The ancient Greek physician Hippocrates (460–370 BC), also known as the “Father of Medicine,” first differentiated the benign and malignant tumors by introducing the terms carcinos and carcinomato describe non-ulcer forming (benign) and ulcer-forming (malignant) tumors.
The word carcinoma in Greek stands for crab.
Most probably, the disease was symbolized with crabbecause of its finger-like tendency to spread throughout the body.
Celsus, an ancient Roman physician (28 BC-50 AD) translated the Greek word carcinoma into cancer (means crab in Latin).
Since then, several hundred of years no notable progress on understanding and treatment of cancer was made until 1775 when Percivall Pott (a British physician) noticed that a number of young boys employed as chimney sweeps developed cancer of the scrotum in later life.
He suggested the presence of something in the soot which caused cancer.
Therefore, the concept of carcinogen (cancer causing agent) was developed (Rothschild et al., 1998, 1999, 2003; Faguet, 2014).
With the progress of research and consequently with better understanding the meaning of carcinoma has been modified and presently it denotes the cancer arising in epithelial cells that cover external and internal body surfaces; approximately 90% of all human cancers are of this type.
Also many other commonly used terms have been developed e.g., sarcoma (cancer arising in mesenchyme-derived tissue supporting tissue) which includes cancers of bone, cartilage, fat, connective tissues and muscle; lymphoma cancer arising in the lymph nodes and tissues of the immune system, leukemia (cancer of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream), adenoma (cancer of glandular epithelium, in Latin adeno means gland) etc.
Cancer is the leading cause of death in developed countries and the second leading cause of death (after cardiovascular and related diseases) in developing countries3 and accounted for 8.2 million deaths in 2012 among which 70% occur in low- and middle-income countries.
According to the World Health Organization the annual cancer cases will rise from 14 million in 2012–2022 within the next two decades4,5.
Cancer can spread in the body following two mechanisms: invasion and metastasis.
According to National Cancer Institute, invasion denotes “the direct migration and penetration by cancer cells into neighboring tissues” whereas metastasis stands for “the ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body”6.
To have a clear understanding, these two mechanisms can be compared with the ways fire can spread in a locality.
When fire spread from one house to its adjacent house the process can be compared with invasion where cancer tissue/cells invade from one tumor to its adjacent body organ and new tumor is formed in that organ.
The spark of fire can also spread from one burning house to a remote house by air (carrier).
This can be compared with the migration of cancer tissue/cells carrying out by blood or lymph to another part of the body (for example from lung to liver) and new tumor is formed in that organ.
Invasion and metastasis are considered as one of the hallmarks in cancer biology.
Although cancer is treated by surgery, radiotherapy, immunotherapy or gene therapy, separately or in combination, still chemotherapy plays crucial role for the treatment of cancer; particularly to inhibit invasion and metastasis.
Therefore, there is a continuous need to search new anticancer agents to prevent invasion and metastasis and subsequently to reduce cancer-related mortality.
Current research in this field directs to identify potent anti-invasive and antimetastatic novel chemotherapeutics.
A qualitative estimate states that about 25% drugs are still directly derived from the Mother Nature and 74-80% of all cancer drugs have their origins in natural products i.e., these drugs are made by natural product modification.
Of the 1355 new entities introduced as therapeutics between 1981 and 2010, 71% were natural products or natural product derived compounds (Hasima and Aggarwal, 2012; Newman and Cragg, 2012).
Curcumin (diferuloylmethane), the major constituent of curcuminoids, is present in turmeric which is the dried powered rhizomes (underground stems) of Curcuma longa Linn of the Zingiberaceae family.
The medicinal use of turmeric (haridra) was indicated in Sushruta Samhita, one of the three fundamental texts of Ayurveda (Indian traditional medicine) in the 6th century BC.
Its medicinal uses were also found in Charaka Samhita (300–500 BC).
As Indian traditional medicine (Ayurveda) turmeric has been using to treat a broad range of common disorders for over 6000 years (Padhye et al., 2010).
In India, turmeric is used as a cooking spice to induce nice yellow-orange color and flavor in curries, pickles and chutneys.
It is used worldwide as a color inducing agent as well as preservative in American mustard, mayonnaise, butter and margarine and has been designated as international food additive E100 (Epstein et al., 2010).
Turmeric is in the GRAS (Generally Recognized As Safe) list of the US Food and Drug Administration having GRN number 4607.
This royal spice was introduced to the western world in the 13th century by Marco Polo, one of the early European explorers to the Indian subcontinent (Aggarwal et al., 2007; Basnet and Skalko-Basnet, 2011).
Since then India is the highest turmeric producing country in the world (Ploto, 2003; Basnet and Skalko-Basnet, 20118).
Turmeric has at least 76 synonyms listed in the 1999 World Health Organization (WHO) monograph (World Health Organization, 1999).
A few popular names are Haridra (Sanskrit), Halood (Bengali), Haldi (Hindi), Kurkum uqdah safra (Arabic), Ukon (Japanese), Chiang Huang (Chinese), Ulgeum (Korean), Kurkuma (German), Safran des Indes (French), kurkumy (Russian), Indian saffron etc.
Besides its culinary appeal turmeric has a glorious history of uses as a therapeutic and preventive agent against a wide array of disorders and diseases, either by itself or in combination with other agents.
As an ancient household remedy a hot poultice of turmeric powder and slaked lime (chun-halood in Bengali) is applied locally to relieve muscular pain and inflammation caused by sprain and injury.
In some parts of India, a drink made from fresh turmeric, ginger roots and honey in a glass of hot milk are given to women twice daily after childbirth.
A poultice of fresh turmeric paste is also applied to the perineum as wound healing for lacerations in the birth canal (Hatcher et al., 2008).
Its traditional uses as strong therapeutic or preventive agents against several human diseases include, but are not limited to, diabetes, fibrosis, asthma, rheumatism, allergies, inflammation, intestinal worms, atherosclerosis, diarrhea, dyspepsia, intermittent fevers, biliousness, cough, sinusitis, constipation, jaundice, urinary discharges, flatulence, leukoderma, amenorrhea, acne, colic inflammation, respiratory ailments, lupus nephritis, irritable bowel syndrome, menstrual difficulties, anorexia, coryza, hematuria, hemorrhage, neurodegenerative such as Alzheimer’s disease as well as cancer (Ammon and Wahl, 1991; Ploto, 2003; Chattopadhyay et al., 2004; Salvioli et al., 2007; Hatcher et al., 2008; Ringman et al., 2012; Gupta et al., 2013b).
The presence of turmeric is essential in most of the religious ceremonies in Hinduism.
Besides the ancient literature, the first scientific report related to the medicinal uses of Curcuma was published in 1748 (Loeber and Buechner, 1748; National Cancer Institute, 1996).
After 67 years a review detailing the biological and medicinal properties of turmeric (curcumin) was published (Vogel and Pelletier, 1815).
In 1937, Oppenheimer reported the medicinal activity of turmeric against biliary diseases (Oppenheimer, 1937).
In 1949, Schraufstatter and Bernt reported (Schraufstatter and Bernt, 1949) the antibacterial activity of curcumin and its pharmacological activity to cure eye disease was reported (Chaudhri, 1950) in the following year. Jiang and co-workers evaluated the anticancer activity of four natural products viz. camptothecin, harringtonin, cantharidin, and curcumin on human tumor biopsies in an in vitro soft agar clonogenic assay system and reported their findings in 1983 (Jiang et al., 1983).
They reported curcumin as “relatively ineffective” antitumor agent than camptothecin and harringtonin.
Probably this was the first evaluation of curcumin against cancer. Kuttan and colleagues published the anticancer activity of curcumin in 1985 (Kuttan et al., 1985).
The acceptance of traditional medicine is considered as an alternative form of modern health care system.
Over the past quarter century there has been growing interest in a possible role of curcumin on various diseases.
The research topic “curcumin” in any chemistry/health related search engine hits a huge number of results, including research articles, reviews, communications, patents, books, editorials etc.
Comparative results obtained up to December 31, 2013 from the two major chemistry and health related databases viz. SciFinder Scholar and PubMed Central are presented in Figure Figure11.
Comparative literature on research with Curcumin.
The presence of about 235 compounds have been identified in turmeric of which 109 sesquiterpenes, 68 monoterpenes, 22 diarylheptanoids and diarylpentanoids, 8 phenylpropene, and other phenolic compounds, 5 diterpenes, 4 sterols, 3 triterpenoids, 2 alkaloids, and 14 other compounds.
Among the diarylheptanoids 3 are curcuminoids, the major pharmacologically active ingredients of turmeric. Curcumin, the major curcuminoid which constitutes 3–5% of turmeric has been consumed for medicinal purposes for thousands of years (Goel et al., 2008; Gupta et al., 2013b). Two other curcuminoids are demethoxycurcumin and bis-demethoxycurcumin (Figure (Figure2).2).
Commercial curcumin is a mixture of three curcuminoids: curcumin (71.5%), demethoxycurcumin (19.4%) and bis-demethoxycurcumin (9.1%) (Gupta et al., 2013b).
Structure of Curcuminoids: The active principle in turmeric.
The isolation of curcumin, the principal constituent of turmeric responsible for its vibrant yellow-orange color, first reported in 1815 (Vogel and Pelletier, 1815) from the plant Curcuma longa as “yellow coloring-matter” and named as curcumin.
Later, it was found to be a mixture of resin and turmeric oil (Gupta et al., 2012).
Curcumin was isolated in 1842 but the chemical formula was not reported (Vogel, 1842; Gupta et al., 2012).
The chemical structure of curcumin as diferuloylmethane was identified by Milobedzka et al. (1910) and the first synthesis of curcumin was reported from the same laboratory in 1913 (Milobedzka et al., 1910; Lampe and Milobedzka, 1913; Gupta et al., 2012).
In 1953, Srinivasan reported the chromatographic resolution and quantification of curcumin from curcuminoids (Srinivasan, 1953).
The chemical structure of curcumin was confirmed in 1973 (Roughley and Whiting, 1973) and a few years ago in 2007, its solution structure (Payton et al., 2007) was reported (Figure (Figure33).
Figure 3
Milestones in Curcumin research.
Since the publication of the preliminary investigations on the anticancer activity of curcumin as a promising anticancer agent in the mid-eighties (Jiang et al., 1983; Kuttan et al., 1985), scientists from all over the world have been paying their attention to this novel nutraceutical.
It is now well known that cancer is neither a single disease nor a comparatively new disease. It has already been mentioned that invasion and metastasis are two major problems for the treatment of cancer.
Curcumin has successfully demonstrated its potential to act as a potent anti-invasive as well as anti-metastatic agent in vitro, ex vivo and in vivo in numerous occasions. It can inhibit cancer cell migration and invasion by manipulating several signaling pathways as described in the sequel.
More information: Naboneeta Sarkar et al, Liposome-Encapsulated Curcumin-Loaded 3D Printed Scaffold for Bone Tissue Engineering, ACS Applied Materials & Interfaces (2019). DOI: 10.1021/acsami.9b01218
Journal information: ACS Applied Materials and Interfaces
Provided by Washington State University
