REVIEW Bali Medical Journal (Bali MedJ) 2021, Volume 10, Number 2: 608-616 P-ISSN.2089-1180, E-ISSN: 2302-2914 The potential effect and delivery of piperine on chemoresistant breast cancer Published by Bali Medical Journal Desak Made Wihandani1*, I Putu Gede Septiawan Saputra2, Ni Putu Sri Indrani Remitha2, Anak Agung Bagus Putra Indrakusuma2, Putu Anda Tusta Adiputra3, I Gede Putu Supadmanaba1 1Department of Biochemistry, Faculty of Medicine, Universitas Udayana, Bali, Indonesia ABSTRACT 2Undergraduate Student, Faculty of Medicine, Universitas Udayana, Bali, Breast cancer is the most common malignancy in women worldwide. Breast cancer is associated with a high mortality rate Indonesia and health-related economic burden. Breast cancer patients have a low 5-year life expectancy when diagnosed at advanced 3Division of Surgery Oncology, Department of Surgery, Faculty of stages. Besides, the emergence of chemoresistance in breast cancer has led to an intense search for alternative anticancer Medicine, Universitas Udayana, Sanglah agents. One of the potential anticancer compounds is Piperine. Several studies had found that Piperine has anticancer General Hospital, Denpasar, Bali, effects such as anti-proliferation, induces apoptosis, anti-migration or anti-metastasis, chemo-enhancer or chemosensitizer, Indonesia cytotoxic agents, anti-angiogenesis, immune response modulators, and self-renewal inhibitor for cancer stem cells. Several delivery agents such as PLGA, PEG-PLGA and liposomes have been studied to improve Piperine’s delivery and have shown *Corresponding to: good results. Therefore, the combination of Piperine and nanoparticles is a potential anticancer agent, especially in breast Desak Made Wihandani; Department cancer. of Biochemistry, Faculty of Medicine, Universitas Udayana, Bali, Indonesia; [email protected] Keywords: breast cancer, chemoresistance, delivery, effect, Piperine Cite This Article: Wihandani, D.M., Saputra, I.P.G.S., Remitha, N.P.S.I., Indrakusuma, A.A.B.P., Adiputra, P.A.T., Supadmanaba, Received: 2021-02-05 I.G.P, I.B.P. 2021. The potential effect and delivery of piperine on chemoresistant breast cancer.Bali Medical Journal 10(2): Accepted: 2021-06-30 608-616. DOI: 10.15562/bmj.v10i2.2247 Published:2021-07-16 INTRODUCTION characteristics that are resistant to MOLECULAR BASIS OF several types of chemotherapeutic Breast cancer is the most common CHEMORESISTANCE IN BREAST agents. Therefore, several recent studies CANCER malignancy in women, responsible for have focused on finding new anticancer 25% of all cancer worldwide. According agents that have good effectiveness or can Chemoresistance is a crucial evolution in to GLOBOCAN (IARC), in 2018, there increase the therapeutic effectiveness of cancer progression, and it heavily influences were 2,088,849 new breast cancer cases the patient’s prognosis.9 Drug resistance 1 chemotherapeutic agents when combined. with 626,679 mortality. In Indonesia, the One of the compounds that have is classified into acquired resistance and incidence of breast cancer was recorded at potential anticancer effects is Piperine. intrinsic resistance.10 Chemoresistance 40 per 100,000 populations, with mortality in breast cancer occurs due to various 2 Piperine is an alkaloid class compound at 16.6 per 100,000 population. According that is found in many plants from the factors in different mechanisms, such as to Riskesdas 2018 data, the incidence of Piperaceae family. It is most commonly transport and excretion, cell metabolism, breast cancer in Bali Province reaches tumor microenvironment, cancer stem 3 found in black pepper (Piper nigrum 0.6 per 1000 women. Breast cancer also L), widely found in Indonesia.6 As an cells, cancer signaling pathways, the role responsible for a significant health-related anticancer agent, Piperine can induce cell of miRNA, cell membranes, and others economic burden for the patients and the cycle arrest, inhibit angiogenesis, inhibit lain.11 The relationship between the nations. According to Barron et al. and metastasis, and induce apoptosis of cancer role of miRNA, JAK / STAT3 pathway, Sun et al., the economic burden of breast cells.7 However, Piperine is unstable, has and the tumor microenvironment in cancer ranges from 29,000 - 62,000 US chemoresistance breast cancer is the focus 4,5 low bioavailability, insoluble in water, dollars. and difficult to absorb.8 Therefore, a of its considerable effect. The life expectancy of breastdelivery strategy is needed to enhance the Several miRNAs are known as cancer patients is considered good, bioavailability of Piperine. In this review, oncogenes and can influence cancer but it continues to decline as the stage progressions such as tumor initiation, 1 the potential anticancer effect of Piperine progresses. Also, treatment options will be described along with its delivery tissue invasion, and even metastasis.12 are often limited due to breast cancer mechanism for Piperine. However, evidence showed that 608 Published by Bali Medical Journal | Bali Medical Journal 2021; 10(2):Open 608-616 access: | doi: www.balimedicaljournal.org 10.15562/bmj.v10i2.2247 REVIEW decreased miRNA function increased pathway, overexpression of miR -621 and breast cancer.11 Additionally, the JAK the expression of drug resistance-related miR-383 induce FBXO11 and Gadd45g, / STAT3 pathway has an interesting genes (P-glycoprotein, ABCB1: ATP leading to chemosensitivity), epithelial- mechanism in inducing chemoresistance Binding Cassette Subfamily B Member 1; to-mesenchymal transition or EMT with intrinsic and extrinsic pathways MRP-1: Multidrug Resistance-Associated (miR-489 and miR-125b overexpress capable of regulating lipid metabolism. Protein Group 1 or ABCC1: ATP Binding Smad3 and Sema4C), cancer stem cells It also induced stemness when inhibited, Cassette Subfamily C Member 1; BCRP: (CSC) (decreased miR-34a function reset leading to chemoresistance in breast Breast Cancer Resistance Protein or genes NOCTH1, miR-7 influence CSC cancer by blocking self-renewal (Figure ABCG2: ATP Binding Cassette Subfamily for metastasis by inducing the KLF4 1B).21 G Member 2), DNA repair (miR-206 gene) (Figure 1A).12–20 Accordingly, Wnt, An enzyme essential for fatty acid increases BRCA1 expression and induces Hippo, Notch, Hedgehog s, JAK / STAT3 β-oxidation (FAO) is associated with a Cyclin D2), apoptosis resistance (miR- pathway, and PI3K / Akt / mTOR signaling diverse lipid metabolism gene expression, 149 controls NDST1 and activates HS are also overexpressed in chemoresistant carnitine palmitoyltransferase 1B (CPT1B).22 FAO produces NADH and FADH2 to reduce oxidative stress and increase ATP and Acetyl Co-A, affecting protein acetylation, the TCA cycle, and fatty acid synthesis.23,24 The enzymes are closely related to Acetyl Co-A, and decreased expression suppresses metabolic acetylation, stopping breast cancer stem cells (BCSCs) and metabolism related to proliferation.24,25 Breast adipocytes trigger leptin fatty acid to control CPT1B- induced STAT3, also reset FAO activity in BCSC (Figure 1B).21 The tumor microenvironment also plays a crucial role in determining the efficacy of chemotherapeutic agents.26 Tumor microenvironment affects interstitial tissue, extracellular matrix, and normal stromal cells. Chemoresistance in breast cancer is associated with cancer- associated fibroblast (CAF), endothelial- cell vascularization, tumor-associated macrophage (TAM), fibroblasts, and mesenchymal stromal cell (MSC). Cancer cells regulate TAM and vice versa.27,28 TAM can differentiate into M1 (anti- cancer macrophage) and M2 (pro- cancerogenic).29 Cancer cells secrete transforming growth factor-β (TGF-β) and growth factors which induce angiogenesis and affecting endothelial cells.26 Reversely, MSCs also influence cancer cells and inducing TGF-β production even further.30 Figure 1. Pathogenesis of chemoresistance breast cancer. A. Role of miRNA in chemoresistance On the other hand, T regulator (Treg) breast cancer. Decreased miRNA function increases the number of induced genes, leading to chemoresistance.12 B. JAK / STAT3 pathway. This signaling inhibits natural killer (NK) cells through 31 pathway regulates fatty acid β-oxidation (FAO) and promotes chemoresistence.21 CCL-2 and helps in cancer progression. C. Interaction of tumor microenvironment with breast cancer cells against Fibroblasts (a major component of the chemotherapy agents. NK: natural killer, APC: adenomatous polyposis coli, CAF: tumor microenvironment) are considered cancer-associated fibroblast, CXCL12: chemokine (CXC motif) ligand, NF: normal the major player in chemoresistance. fibroblast, TGF-β: transforming growth factor-beta, MSC: mesenchymal stem cells, CAF modulates normal fibroblast (NF), VEGF: vascular endothelial growth factor, IL: interleukin, CCL: chemokine (CC altering cancer vascularity and immune motif) ligand, M1 and M2: anti-tumorigenic, TAM: tumor-associated macrophage, cells (Figure 1C).32 M-CSF: macrophage colony-stimulating factor.11 Published by Bali Medical Journal | Bali Medical Journal 2021; 10(2): 608-616 | doi: 10.15562/bmj.v10i2.2247 609 REVIEW THE CHEMISTRY NATURE OF associated amide and Piperine. Pure PLGA Nanoparticle PIPERINE Piperine can also be produced by Various literature has demonstrated supercritical fluid extraction followed by the potential of Poly (lactic-co-glycolic Piperine is one of the alkaloid compounds crystallization of ethanol. In general, the acid) (PLGA) nanoparticles as a drug commonly found in the plant from the supercritical fluid