EP-4739320-A1 - ANTI-CANCER EFFECT OF THE COMBINATION OF SODIUM PENTABORATE PENTAHIDRATE AND VITAMIN D ACTIVE FORM CALCITRIOL AGAINST HEPATOCELLULAR CARCINOMA

Abstract

This invention relates to a formulation comprising a combination of sodium pentaborate pentahydrate and calcitriol, the active form of vitamin D, which shows anti-cancer effect when used in the treatment of hepatocellular carcinoma. The object of the invention is to provide an anti-cancer effect against hepatocellular carcinoma by a formulation obtained from the combination of sodium pentaborate pentahydrate and calcitriol.

Inventors

• SAHIN, FIKRETTIN
• OMEROGLU ULU, Zehra
• DEGIRMENCI, Nurdan Sena
• PADAR, Gamze

Assignees

• Yeditepe Universitesi

Dates

Publication Date

20260513

Application Date

20240806

Claims (2)

1. 1. A formulation for the treatment of hepatocellular carcinoma comprising sodium pentaborate pentahydrate (NaB: B 5 Hi 0 NaOi3) and calcitriol (1 ,25(OH) 2 D 3 ), the active form of vitamin D, and inducing apoptotic cell death in human hepatocellular cancer cell line HepG2 (HB-8065, ATCC) cells upon treatment.
2. 2. A formulation according to claim 1 comprising the dual combination of 1000 pg/ml NaB and 1 pM calcitriol.

Description

ANTI-CANCER EFFECT OF THE COMBINATION OF SODIUM PENTABORATE PENTAHIDRATE AND VITAMIN D ACTIVE FORM CALCITRIOL AGAINST HEPATOCELLULAR CARCINOMA Technical Field This invention relates to a formulation comprising a combination of sodium pentaborate pentahydrate and calcitriol, the active form of vitamin D, which shows anti-cancer effect when used in the treatment of hepatocellular carcinoma. Prior Art Hepatocellular carcinoma (HCC) is the 5th most common type of primary malignant liver cancer of epithelial origin, ranking 3rd in terms of mortality. Chronic liver disease and cirrhosis are the main risk factors for hepatocellular carcinoma. In addition, Hepatitis B and C viruses, excessive alcohol intake, obesity, and diabetes are the leading risk factors worldwide [1]. HCC is generally two to four times more likely to occur in men than in women [2], In 2020, approximately more than 900,000 people were diagnosed with HCC [3]. The disease being asymptomatic in the early stages prolongs the time it takes for patients to be diagnosed and causes late stages diagnoses after cirrhosis. The survival rate after diagnosis ranges from approximately 6 months to 20 months [4], Hepatocellular carcinoma treatments are decided based on the Barcelona Clinic Liver Cancer (BCLC) system depending on tumor stages, size, liver functions and expected benefits after treatment [5]. While resection, transplantation and local ablation are preferred for HCC patients in the early stage, TARE method can be preferred for patients in the moderate stage and systemic treatments can be preferred for patients in advanced stages (6). Since 80-90% of cases are diagnosed at a late stage, most of the treatment methods are very limited, and due to insufficient proven studies on tumor recurrence after treatment, recurrence is encountered within 5 years in most HCC patients [7], Therefore, there is still no effective treatment for HCC. Boron is a biologically important element that has been found to affect many mechanisms in animals and plants. Extensive research is being carried out using the boron element in the clinical studies of various diseases. Research has shown that boron accelerates wound healing and is anti-inflammatory [8]. The anti-cancer effects and cancer growth inhibitory properties of different boron derivatives have been proven in many different types of cancer such as hepatocellular and colorectal cancer [9, 10], lung cancer [11], prostate cancer [12], and breast cancer [13]. Bortezomib, a boronic acid derivative, is a boron-derived drug approved by the FDA for the first time showing proteasome inhibitory properties [14], The effects of bortezomib on HCC have been shown in studies to be anti-proliferative and pro-apoptotic, however, since HCC can rapidly gain resistance to the drug, future studies focus on combining Bortezomib with different substances and increasing its effect (15). Sodium pentaborate pentahydrate (NaB), a boron derivative, has also been found to have an anti-cancer effect in assays conducted with lung cancer cell lines [16]. Furthermore, other studies have shown that NaB has anti-microbial and anti-viral effects [17], Vitamin D is a compound belonging to the group of fat-soluble vitamins, the majority of which can be synthesized in human skin as a result of sun exposure. Some of its most important functions in the body are its relationship with the mechanism of calcium and phosphate [18]. The two main forms of vitamin D important for humans are vitamin D2 (ergocalciferol) of plant origin and cholecalciferol, vitamin D3 of animal origin, which is derived from 7-dehydrocholesterol in the skin. The liver has a huge role in the synthesis of vitamin D in the body. Ultraviolet-B rays in the sun rays convert the 7- dehydrocholesterol in the skin into previtamin D3, and then this intermediate quickly forms vitamin D3, depending on the temperature. Since the synthesized vitamin D3 is not biologically active, it is transported to the liver with the help of vitamin D-binding proteins in the blood. Vitamin D3 that reaches the liver is converted to 25-(OH)D3, then transported to the kidney and converted into 1 ,25-(OH)2D3 (calcitriol), the active form of vitamin D. This is the main circulating form of vitamin D found in the body [19, 20, 21], In studies on vitamin D, its protective and healing effects against diseases such as cancer, diabetes, heart diseases, immune system, and bone diseases have been observed [22], According to in vitro and in vivo research, vitamin D can reduce the development of tumors and prevent the growth of cancer cells. It also has antiinflammatory, immunomodulator, pro-apoptotic, and anti-angiogenic properties [23]. For this reason, cancer research with vitamin D has increased rapidly. When the relationship between HCC and vitamin D was examined, vitamin D deficiency was seen in HCC patients, and its potential therapeutic effects were mentioned (24). Combination therapy studies are an important type