Phytochemical and Pharmacology Effect of Calotropis Gigantea as Anti-Cancer Therapy: Systematic Review

The high prevalence of cancer in the world makes many researchers look for alternative therapies that can be used to treat cancer. One of them is by using traditional plants, namely Calotropis gigantea R.Br. This is due to the presence of alkaloids, glycosides and tannins in plants that function as anticancer. The purpose of this study was to dig deeper into information related to the phytochemistry and pharmacology effect of Calotropis gigantea as an anticancer therapy, and can be used as a reference for the development of traditional medicines. The method used is PRISMA ( Preferred Reporting Items for Systematic Reviews and Meta-analyses ), with inclusion and exclusion criteria, 11 articles were selected for review. The results showed that Calotropis Gigantea contains Calotropin, Calotroposide A, oxypregnane oligoglycoside compounds which have activity in inhibiting cancer cell growth through the mechanism of apoptosis induction and ROS inhibition. From this systematic review, it can be recommended that the plant Calotropis gigantea can be further developed into standardized herbal medicine and phytopharmaceuticals.


Introduction
Cancer is a disease caused by uncontrolled cell growth and can be cured if diagnosed early (Mathur, 2015). Cancer in Indonesia itself has a high mortality rate. Based on data from the International Agency for Research on Cancer (IARC) shows that in 2020 there are 234,511 cancer deaths, with a total of women experiencing cancer more than men (IARC, 2020). The high prevalence of cancer in the world makes researchers interested in using traditional plants because side effects are smaller than chemotherapy treatment (Rahman, 2015).
One of the plants that can be an alternative cancer treatment is Calotropis gigantea R.Br. Calotropis gigantea R.Br. is a wild plant found in several areas of India, Indonesia, Malaysia, Thailand, and Sri Lanka, China. This plant belongs to the Apocynaceae family and is a latexproducing plant. Calotropis gigantea is known for its various traditional medicinal properties to cure various diseases. This plant is reported to have analgesic activity, antimicrobial activity, antioxidant activity, antipyretic activity, insecticidal activity, cytotoxicity activity, 1 st International Pharmacy Ulul Albab Conference and Seminar (PLANAR) hepatoprotective activity, laxative activity, procoagulant activity and wound healing activity .
Supported by the results of Padhi's research, (2019) it was found that on phytochemical screening and anticancer activity ofleaf extract Calotropis gigantea (L.) Dryand. revealed that the presence of alkaloids, glycosides and tannins in plant leaves that function as anticancer (Avinash, 2019). The purpose of this literature review is to dig deeper into information related to the phytochemistry and pharmacology of Calotropis gigantea as an anticancer therapy, and can be used as a reference for the development of traditional medicines.

Method
The research method used is PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses). This study uses articles from the Google Scholar, Pubmed and Elsivier databases published from 2016-2021. The keywords used were Calotropis gigantea, anticancer, pharmacotherapy and phytochemicals. The inclusion criteria used in this study were Indonesian or English articles, articles published in 2016-2021, original articles. As for the exclusion criteria, namely publications outside the years 2016-2021, Systematic review.

Taxonomic
Classification Taxonomic classification Calotropis gigantea L according to Singh (1996)

Plant morphology
Leaf Calotropis gigantea has a single leaf, which are arranged opposite, oval or elliptical, shortstemmed, grows face. pale green in color and has a fairly large size of about 30x25 cm .

Flowers
Compound, bisexual, pale rose in color, purple or greenish yellow and have a faint odor. The flower buds are ovate, green petals, and long flower stalks .

Bark & Branches
The bark is thick, leathery and yellow to brown in color, the twigs are green and fleshy and may have a tomentum covering (white fur like hair) .

Inflorescences
The inflorescences emerge from the base of the leaf in the pedunculate (7cm) .

Fruits
The fruits are green ovate (follicle), up to 15 cm long by 10 cm wide. when split to release feathers, light brown thin seeds with white filamentous pappus up to 6cm long on one side. The flowering period is from March to October .

Distribution of geography
Calotropic gingantea is distributed in tropical and sub-tropical areas of Asia and Africa. In India it is represented by two species namely, C. procera and C. gigantea. C. procera is more common in southwest and central India and western Himalayas whereas C. gigantea is abundant throughout India directly from the Himalayas to southern India (Ahmed, 2016).
The search results for articles using the keywords Calotropis gigantea, anticancer, pharmacotherapy and phytochemicals from the Google Scholar database, Pubmed, Elsivier (n = 1564). Screening of articles by title and abstract (n=86). The excluded articles did not meet the inclusion criteria (n = 56). Screening of articles based on full text and eligibility criteria (n = 19). So that 11 selected articles were obtained for review. Produced an anticancer effect value of (10µL, 5 mg/mL).  MTT test on breast cancer cells T47D

Discussion
Common cancer treatments such as surgery (surgery), chemotherapy (including immunotherapy and hormone administration) and radiotherapy have not given satisfactory results and have several weaknesses, so an alternative for anticancer treatment is sought (Setiawan, 2015). One of them by utilizing traditional plants.

Anticancer activity of compounds in the leaves
Previous studies have reported that the leaves are known to contain compounds belonging to the group of alkaloids, glycosides and tannins. The compounds are known to inhibit the growth of cancer cells through induction of apoptosis pathway activation of the extrinsic and intrinsic, inhibition of cell cycle, and the generation of ROS (Padhi, et al, 2021;Lee, 2019).

Activities anticancer compounds in the Flower
Activities anticancer in this part of the flower Calotropis gigantea are compounds extract methanol and chloroform fraction. The results showed that the cytotoxic potential against breast cancer cells (MDAMB231) with IC50 values of hexane and methanol extract obtained 84.05 g/mL and 72.27 g/mL, respectively (Amutha, et al, 2020).

Anticancer activity of compounds in The bark
ethyl acetate fraction in the bark of theplant Calotropis gigantea contains Calotroposides (oxypregnane oligoglycosides). It was also reported that the ethyl acetate fraction had higher anticancer activity than ethanol extract (Mahar., et al, 2016). Other studies reported thatextract dichloromethane had anticancer activity with mechanism to increase the induction of apoptosis (Thanwarat et al, 2021).

Anticancer activity of compounds in roots and stems
The roots of Calotropis gigantea have been reported to contain Calotroposide A compounds that are able to inhibit the growth of colon cancer cells (WiDr cell line) at IC50 17.23μg/ ml (Mutiah, et al, 2018). Roots have also been reported to have high potency in T47D breast cancer cells. This effect was evidenced by the inhibition value of the ethanolic root extract (IC50 89.76 g/mL) which was higher than that of the leaf extract (IC50 459.51 g/mL) and flower extract (IC50>1000). This shows that the root extract has a high potential for inhibiting the growth of breast cancer . It was also reported Extract Methanol stems have anticancer potential with a value of inhibition of 5mg / mL (Immaculate et al., 2020).

Conclusion
The results of this study showed that the plant Calotropis gigantea containing compounds Calotropin, Calotroposide A, oxypregnane oligoglikosida that had activity in inhibiting the growth of cancer cells through the mechanism of apoptosis induction and ROS inhibition. From this systematic review, it can be recommended that theplant Calotropis gigantea can be further developed into standardized herbal medicines and phytopharmaceuticals.