Potential of Bidara Leaf as Adjunctive Therapy against Breast Cancer Cell Line: A Review

Ifuling Audrein Yansen¹, Theresia Indah Budhy^2,3, Alexander Patera Nugraha^2,4,5*,

Florentina Joestandari⁶, Tengku Natasha Eleena binti Tengku Ahmad Noor^7,8

¹Graduate Student of Immunology, Post Graduate School, Universitas Airlangga, Surabaya 60115 Indonesia

²Immunology Study Program, Postgraduate School, Universitas Airlangga, Surabaya 60115, Indonesia

³Department of Oral and Maxillofacial Pathology, Faculty of Dental Medicine,

Universitas Airlangga, Surabaya 60115, Indonesia

⁴Department of Orthodontics, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60115, Indonesia

⁵Graduate Student of Dental Health Science, Faculty of Dental Medicine,

Universitas Airlangga, Surabaya, Indonesia

⁶Faculty of Dentistry, Institute of Health Bhakti Wiyata, Kediri, Indonesia

⁷Membership of Faculty of Dental Surgery, Royal Collage of Surgeon, Edinburgh University, United Kingdom

⁸Malaysian Armed Forces Dental Officer, 609 Armed Forces Dental Clinic,

Kem Semenggo, Kuching, Sarawak, Malaysia.

*Corresponding Author E-mail: alexander.patera.nugraha@fkg.unair.ac.id

ABSTRACT:

Background: Breast cancer or Carcinoma mammae is a malignancy that damage the gland ducts, and breast supporting tissues. Breast cancer is ranked first as a malignancy that often occurs in the world. The majority of women with breast cancer will have many surgeries. Chemotherapy is frequently used in conjunction with surgery. However, the side effects of chemotherapy drugs can damage healthy cells.  Bidara leaf are one of the most promising sources of bioactive compounds for the pharmaceutical field in the treatment of breast cancer. Aims: This review article aims to describe the several types of Bidara leaf that contain compounds and anticancer activity that have potential as alternative treatments for breast cancer through narrative review. Review:This review article discusses several types of Bidara leaf and their anticancer activity. Conclusion: From the results of a journal review, it was found that several types of Bidara leaf with breast anticancer activity were Ziziphus spina christi, Zizyphus mauritiana, Ziziphus nummularia, with various activities such as cytotoxicity, antiproliferative, proapoptotic, and proinflammatory on the MCF-7 breast cancer cell line.

KEYWORDS: Cancer, Bidara leaf, Medicine, Cytotoxic, Non-communicable disease.

INTRODUCTION: 

Breast cancer is an uncontrolled and irregular growth of breast cells.¹ Breast cancer can also spread to other organs. Most tumor cells originate from the epithelium of the breast ducts and lobules, especially in the terminal duct-lobular unit and more than 75% are invasive ductal carcinoma not otherwise specified (IDC-NOS).

The most common locations for metastases in breast cancer are lung and pleura (15-20%), bones (20-60%), liver (5-15%), brain (5-10%) and local metastasis/ regional (20-40%).^2,3

Breast cancer is a heterogeneous disease with different tumor subtypes, which are generally based on hormone receptor (HR) and HER2 expression (eg luminal, HER2, and triple-negative subtypes). These subtypes differ in their biology, prognosis, treatment strategy, and pattern of metastasis.⁴ The causes of breast cancer are very multifactorial and influence each other, namely several endogenous and exogenous factors as well as the interaction of genetic factors. About 95% of cancers can be attributed to lifestyle and inflammation as the underlying cause.⁵

The incidence and mortality in breast cancer patients continue to increase every year. The prevalence of incidence of 8-9% of women experiences breast cancer. More than 250.000 new cases of breast cancer are diagnosed every year worldwide, in Europe approximately 175.000 cases and more than 165.000 patients die if not treated properly. In the United States, 44.000 patients died of breast cancer.⁶ According to the World Health Organization (WHO), 2.3 million women will be diagnosed with breast cancer in 2020, with 685,000 fatalities worldwide. Breast cancer will have been diagnosed in 7.8 million living women in the last 5 years by the end of 2020, making it the most frequent cancer in the world. More than half of all breast cancer deaths occur in Asia, with Southeast Asia accounting for 15% of all deaths.⁷In Indonesia, more than 80% of cancer cases are discovered to be advanced.⁸

It has long been known that the induction of apoptosis in cancer cells by natural compounds is the main target for cancer prevention and therapy. Apoptosis is an active and highly regulated form of cell death in which damaged and mutated cells, potentially harmful to entire organisms, are naturally eliminated without causing any adverse side effects. Therefore, the identification of natural products based on the mechanism of action can play an important role in the development of new alternative chemotherapy drugs. Natural products serve as important chemical prototypes for the discovery of new molecules and continue to be the main source of the most promising drugs, especially in the anticancer field.^9-11

Bidara leaf (Zizipus sp.) have been scientifically proven to contain several phytochemicals with significant anti-cancer properties. Research on hexane and ethanol fractions of bidara leaves found the presence of alkaloids, saponins, terpenoids and steroids which have strong radical scavenging activity, cancer growth inhibitory effet and exert anti-carcinogenic effects by regulating Reactive Oxygen Species (ROS) levels, signal transduction cascade, angiogenesis, and cell proliferation.¹² Furthermore, this review article aims to describe the several types of Bidara leaf that contain compounds and anticancer activity that have potential as alternative treatments for breast cancer through narrative review.

METHOD:

The data for this journal review was gathered through the literature study approach, which included both primary and secondary libraries. The library search was conducted utilizing online library search tools including NCBI-PubMed and Google Scholar.The keywords used for the literature search were related to “breast cancer”, “Bidara leaf and breast cancer”, “anticancer activity Bidara leaf”, “Zizipus sp. with breat cancer cell line” and “Bidara leaf and breast anticancer activity”. The database libraries that have been obtained are then arranged according to the framework, data on bidara leaf with anticancer activity are arranged in tabular form, and journal reviews are written according to the given format. From the results of the literature study, 20 journals from 2020 and 2021 contained information about bidara leaf with anticancer activity, which will be shown in table 1 as well as several sources containing information about the condition of breast cancer in Indonesia.

RESULTS:

According to the results of literature study, 20 articles were obtained, and only 5 articles that really explained the potential of bidara leaf against breast cancer. Besides, research on the potential of bamboo shoots as an anti-breast cancer agent is still rare. The 2 articles validated from 2016 to 2021 containing information about bidara leaf with anticancer activity, which will be shown in Table 1. as well as several sources containing information about the condition of breast cancer in Indonesia.

Table 1: Bamboo Shoots And Anti-Breast Cancer Activity.

No	Class	Types Of Bamboo	Metabolites (Compound Content)	Cell Line	Mechanism	Sources
1	Dicotyledonae	Ziziphus spina christi	B-Sitosterol Triterpenoid, Ploliphenol	MCF-7	Cytotoxic effect, antiproliferative avtivity and proapoptotic activity	Fatemeh Farmani, et al.,2016.^9
2	Dicotyledonae	Zizyphus mauritiana	Terpenoid, Phenol,sterol, flavonoid	SKBR3	Cytotoxic activity against human breast adenocarcinoma cell line (MCF-7) and antiproliferative activity	Qudsia Tabassam, et al., 2021.^10
3	Dicotyledonae	Ziziphus spina-christi	B-Sitosterol Triterpenoid, Ploliphenol	MCF-7	Proapoptotic activity by inducing (Bax and Bcl2 genes expression levels)	Ahmadi R, et al., 2017.^11
4	Dicotyledonae	Ziziphus nummularia	Terpenoid, kuersetin	T-47D	Inhibits the growth of the T-47D cell line	Hemali Padalia and Sumitra Chanda., 2021.^13

Bidara leaves (Zizipus sp.) have become an alternative choice to treat cancer. Studies have been conducted to determine the active compounds of sea sponges and to prove the anticancer activity of the breast. Some types of bidara leaves are as follows:

1. Ziziphus spina christi:

Research conducted by Farmani, et al. (2016) proved that the Ziziphus spina christi ethanol fraction exhibited antiproliferative properties in MCF-7 cells by inducing apoptosis and discontinuation of G1/S phase cells. Where the results of the annexin-V test for apoptosis showed that the ethanol fraction induces apoptosis in MCF-7 cells after 48hours of incubation at a concentration of 1/2 IC50. In this study, the ethanol fraction showed no significant changes in Bax or Bcl-2 expression at the protein level indicating an independent mitochondrial apoptotic pathway induced by the ethanol fraction.⁹

2. Zizyphus mauritiana:

The results of an study conducted by Tabassamet al. (2021) show that Zizyphus mauritiana extract is a productive source of phytochemicals  that have great potential to inhibit the growth of cancer cells. Furthermore, the results of the invitro test showed that % of confluence decreased at a higher value in SKBR3. This indicates the presence of itotoxic activity, inhibition of proliferation and induction of apoptotic in breast cancer cells.¹⁰

3. Ziziphus nummularia:

Based on research conducted by Chanda and Padalia (2021) proved Ziziphus nummularia shows cytotoxic effects on breast cancer cells. In the test of cell viability showed a decrease in % viability of cells to normal fibroblast cells compared to breast cancer cells. The results showed that the synthesized AgNP had fewer cytotoxic effects on normal cells compared to cancer cells. Cytotoxic effect nanoparticles occur because in reactive oxygen species (ROS) genes damage the intracellular components of cells through oxidative stress and induce apoptosis of cell death.¹³

DISCUSSION:

Very strong cytotoxicity test has an IC₅₀ of less than10 μg/mL, strong cytotoxicity has an IC50 value between 10–100μg mL, and moderate cytotoxicity has an IC₅₀ value between 100-500μg/mL.¹⁴ In addition to the cytotoxicity test, anticancer testing can also be carried out with antiproliferative tests, apoptosis tests, and antimetastatic tests. In the test of anticancer activity with antiproliferative testing carried out by the MTT Assay method.^15-16 Apoptotic testing was carried out by testing the level of cell death due to apoptosis induction by the chemotherapy agents used.¹⁷ Antimetastatic testing is carried out by suppressing cell growth so that it does not metastasize to other organs by counting the number of cell migrations.¹⁸

Breast cancer is the most common invasive cancer in women worldwide and the second leading cause of cancer death, after lung cancer.¹⁹ Breast cancer when it enters an advanced stage or stage III can lead to metastasis or the spread of cancer cells to other parts of the body so that treatment is difficult, and until now there are still recurrences after surgery, this is due to the nature of cancer cells that spread easily.²⁰ It is estimated that almost a third of patients with newly diagnosed breast cancer are predicted to have metastases and die from metastases. The majority of women with breast cancer will have surgery. Radiation therapy, chemotherapy, hormone therapy, and/or targeted therapy are frequently used in conjunction with surgery.²¹

During chemotherapy, patients will experience unwanted side effects. Chemotherapy side effects occur because chemotherapy medications are extremely powerful and attack both cancer cells and healthy cells, particularly those that divide fast. Side effects might arise during treatment or after it has been completed. Hair loss and even baldness, which can occur during chemotherapy, bone marrow abnormalities, such as diminished hemoglobin, platelets, and white blood cells, making the body weak, weary, short of breath, prone to bleed, and readily infected, are some of the side effects of this therapy. The skin becomes blue/blackened, dry, and itchy; the mouth and throat develop canker sores, feel dry, and have difficulty swallowing; nausea and vomiting; digestive tract pain; hormone production is interrupted; sexual appetite and fertility are reduced. The intensity of chemotherapy side effects is determined by a number of factors, including the type of chemotherapy medicine used, the patient's body condition, weight, age, and psychological state.^22-24

CONCLUSION:

Bidara leaf that have been studied have breast anticancer activity such as Ziziphus spina christi, Zizyphus mauritiana, Ziziphus nummularia with various activities such as antiproliferative, proapoptotic, and proinflammatory in breast cancer cell line such as MCF 7, T-47D, SKBR3. However, the further study is still needed to elucidate the active compound of Ziziphus spina christi, Zizyphus mauritiana, Ziziphus nummulariafor anticancer medicine.

ACKNOWLEDGEMENTS:

Authors would like to thank those who are in the master's program of immunology, our family and the whole staff of Universitas Airlangga who have contributed in helping this review complete.

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Received on 04.01.2023            Modified on 22.04.2023

Accepted on 27.06.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(11):5532-5535.

DOI: 10.52711/0974-360X.2023.00895