Antitumor and radiosensitizing synergistic effects of apigenin and cryptotanshinone against solid Ehrlich carcinoma in female mice

Introduction

Cancer is the second leading cause of death worldwide behind cardiovascular diseases.¹ Modern surgery, chemotherapy, and radiotherapy are the most common types of cancer treatments available nowadays that significantly reduced the cancer mortality.^2,3 A benefit of the radiotherapy is the possibility to apply the ionizing radiation locally, thereby preventing systemic toxicity. However, like chemotherapeutic agents, ionizing radiation does not affect all target cells, which can lead to severe side effects in the surrounding tissue. In addition, a large number of human malignant tumor cells responds poorly to ionizing radiation.⁴ Accordingly, the effect of radiation on tumor tissues can be optimized by adding radiosensitizing agents, in order to achieve a greater degree of tumor damage than expected from radiation only, thus minimizing large doses of radiation and also sparing normal tissues. Most of the routinely used synthetic radiosensitizers are commonly toxic per se, non-selective, and are not tumor specific. Because of their negligible toxicity, herbal drugs have gained attention to replace the highly toxic radiosensitizers.⁴ Apigenin (AP; 4,5,7-trihydroxyflavone), one of the most commonly occurring flavonoids, is found in numerous plants.⁵ Like most flavones, AP possesses antioxidant, anti-inflammatory, and antidepressant properties,^6–8 and several epidemiologic studies indicate that a diet rich in flavones, especially AP, is associated with a decreased risk of various human cancers.⁹ In vitro studies demonstrated that AP suppresses cell growth in a number of human cancer cell lines.^10–13 In addition, AP was reported to suppress prostate tumorigenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model through the phosphoinositide 3-kinase (PI3K)/Akt/forkhead box O (FoxO)-signaling pathway.¹⁴ Cryptotanshinone (CPT), a major terpenoid tanshinone isolated from the roots of Salvia miltiorrhiza Bunge, has been used in traditional Chinese medicine for the treatment of a wide variety of clinical conditions, including acute ischemic stroke, coronary artery disease, hyperlipidemia, and Alzheimer’s disease.^15,16 Several studies documented the ability of CPT to inhibit signal transducer and activator of transcription 3 (STAT3) phosphorylation, arrest the cell cycle, and induce apoptosis in different cancer cell lines.^17–19 CPT has also demonstrated sensitizing effects to a broad range of anticancer agents, including cisplatin and 5-fluorouracil, highlighting its therapeutic potential in the treatment of human cancers.²⁰ This study was undertaken to...