The novel DNA alkylating agent BO‐1090 suppresses the growth of human oral cavity cancer in xenografted and orthotopic mouse models

Abstract

Oral cancer is the fourth-most common cause of death in males and overall the sixth-most common cause of cancer death in Taiwan. Surgery, radiotherapy and chemotherapy combined with other therapies are the most common treatments for oral cavity cancer. Although cisplatin, 5-fluorouracil and docetaxel are commonly used clinically, there is no drug specific for oral cavity cancer. Here, we demonstrated that derivatives of 3a-aza-cyclopenta[a]indene, a class of newly synthesized alkylating agents, may be drugs more specific for oral cancer based on its potent in vitro cytotoxicity to oral cancer cells and on in vivo xenografts. Among them, BO-1090, bis(hydroxymethyl)-3a-aza-cyclopenta[a]indene derivative, targeted DNA for its cytotoxic effects as shown by inhibition of DNA synthesis (bromodeoxyuridine-based DNA synthesis assay), induction of DNA crosslinking (alkaline gel shift assay), and induction of DNA single-stranded breaks (Comet assay) and double-stranded breaks (c-H2AX focus formation). Following DNA damage, BO-1090 induced G1/S-phase arrest and apoptosis in oral cancer cell lines. The therapeutic potential of BO-1090 was tested in mice that received a xenograft of oral cavity cancer cell lines (SAS or Cal 27 cells). Intravenous injection of BO-1090 significantly suppressed tumor growth in comparison to control mice. BO-1090 also significantly reduced the tumor burden in orthotopic mouse models using SAS cells. There was no significant adverse effect of BO-1090 treatment with this dosage based on whole blood count, biochemical enzyme profiles in plasma and histopathology of various organs in mouse. Taken together, our current results demonstrate that B0-1090 may have potential as a treatment for oral cavity cancer.Oral cavity cancer involving the lesions occurred in the tongue, oropharynx and floor of the mouth is a prevalent type of cancer in developing countries such as India, Pakistan, Bangladesh and Taiwan. 1 In south-central Asia, it is the third-most common cancer, with an average incidence rate of 1 to 10 per 100,000 people. The incidence of oral cancer is also increasing in developed countries. 2 The treatments of oral cancer include surgery, radiation or chemotherapy, depending on the stage and nature of the tumor. 3,4 Unfortunately, only marginal improvement is seen in many patients, and a complete cure is often not achieved. Half of the patients diagnosed with oral cancer succumb to death within 5 years, and for those who survive, the quality of life remains poor. 1 Thus, development of a drug specific for oral cavity cancer is needed so that substantial improvement in treatment can be achieved.The cytotoxic and antitumor properties of alkylating agents are due to their ability to covalently bind to DNA. There are two types of DNA alkylating agents, monofunctional and bifunctional agents. Monofunctional alkylating agents mainly damage DNA by forming methylated adducts, whereas the damage induced by bifunctional alkylating agents includes monoadducts, intrastrand crosslinks and interstrand crossli...

Silencing JARID1B suppresses oncogenicity, stemness and increases radiation sensitivity in human oral carcinoma

“…In Taiwan mortality report from the Department of Health indicate that 10 in every 100,000 diagnosed cases die of oral cancer annually, making it the sixth most common cause of cancerrelated mortality [2]. Tobacco smoking, Betel nut chewing and alcohol consumption contribute significantly to the risk of developing oral carcinoma, and are indeed implicated in the unabated incidence of this malignancy especially in Taiwan.…”

AKT serine/threonine protein kinase modulates bufalin-triggered intrinsic pathway of apoptosis in CAL 27 human oral cancer cells

“…Apoptosis involves a cascade of molecular changes such as morphology changes, chromatin condensation, and DNA fragmentation (5,6). Abnormal regulation of apoptosis leads to many human disorders including autoimmune disease and cancer.…”

“…Abnormal regulation of apoptosis leads to many human disorders including autoimmune disease and cancer. Thus, understanding the mechanisms of apoptosis is an important strategy for treatment of cancer (6,7). Several gene products have been demonstrated to be critical in the regulation of apoptosis (8,9).…”

“…Apoptotic characteristics include the appearance of the sub-G 1 population and chromatin condensation and elevated pro-apoptotic protein expression levels, the cytochrome c release and caspase cascade activation (6,10,12). In the current study, we provided evidence that bufalin induced apoptosis in CAL 27 cells in a dose-dependent manner through cell cycle arrest at G 0 /G 1 phase (Fig.…”

“…Cytosolic cytochrome c is further involved in caspase activation. The caspase cascade is a key pathway in apoptotic signal transduction, and can be divided into two types of subfamilies: upstream initiator caspases (caspase-8 and -9) and downstream effector caspases (caspase-3, -6 and -7), which directly induce the final events of apoptosis (6,11,12).…”