Bufalin induces DNA damage response under hypoxic condition in myeloma cells

Abstract

Hypoxia serves a crucial role in the development of drug resistance in various cancer cells. Therefore, many attempts targeting hypoxia are underway to overcome the drug resistance mediated by hypoxia. This strategy is useful for multiple myeloma (MM) cells, as MM cells reside within the bone marrow, where oxygen concentrations are relatively low. A natural compound library was screened to identify compounds exerting cytotoxicity in MM cells under hypoxic conditions. Bufalin exhibited marked cytotoxicity to MM cells under normoxic and hypoxic conditions. No significant toxicity was observed in lymphocytes obtained from healthy donors. Under normoxic conditions, bufalin induced a DNA double strand break (DSB) response, ROS induction and apoptosis within 24 with a rapid response compared with melphalan. Interestingly, the bufalin-induced DSB response was not impaired by low oxygen concentrations while the DSB response by melphalan was reduced. Furthermore, treatment with bufalin abolished HIF-1α expression under hypoxia, suggesting that bufalin exerts cytotoxicity under hypoxia by regulating HIF-1α. These results indicate that bufalin induces apoptosis in MM cells through DSB under hypoxic conditions by inhibiting HIF-1α, suggesting that bufalin could be useful for eradication of drug-resistant MM cells in the hypoxic microenvironment.

Regulation and functions of integrin α2 in cell adhesion and disease

“…Bufalin, a component of traditional Chinese medicine, has been found to induce apoptosis in several types of cancers. 78 , 79 Interestingly, it has been found to suppress cervical cancer tumorigenesis and to enhance paclitaxel therapy by suppressing α2/FAK/AKT1/GSK3β signaling. 80 Furthermore, a component in snake venom called aggretin can bind to integrin α2β1.…”

Bufalin inhibits ovarian carcinoma via targeting mTOR/HIF‐α pathway

“…The natural product Chansu enriched with bufalin has long been used in practice as painkiller, detoxicant and cardioactivator as traditional medicine in East Asia. The antitumour activity of bufalin has been recently reported in multiple cancer types including prostate cancer, gastric cancer, colorectal cancer, lung cancer, breast cancer, endometrial cancer, hepatocellular carcinoma and leukaemia 13‐17 . The mechanism of bufalin is multifaceted 25 .…”

“…The antitumour activity of bufalin has been recently reported in multiple cancer types including prostate cancer, gastric cancer, colorectal cancer, lung cancer, breast cancer, endometrial cancer, hepatocellular carcinoma and leukaemia. [13][14][15][16][17] The mechanism of bufalin is multifaceted. 25 Most of the study found its pro-apoptotic activity via regulation of Bcl-2/Bax and Bcl-X and activation of caspase-9.…”

“…Consequently, JNK activation increased the expression of key factors for autophagy such as autophagy‐related gene 5 (ATG5) and Beclin‐1 12 . There are a number of studies about bufalin antitumour function in different cancers including solid tumour and leukaemia 13‐17 . The mechanism of bufalin on tumour suppression is multifaceted, and no conclusive result is available on the specific and detailed mode of action.…”

“…12 There are a number of studies about bufalin antitumour function in different cancers including solid tumour and leukaemia. [13][14][15][16][17] The mechanism of bufalin on tumour suppression is multifaceted, and no conclusive result is available on the specific and detailed mode of action. There might be a cell type and tissue-specific role for bufalin in the process.…”