Research Article: Potential of Bacillus subtilis lipopeptides in anti-cancer I: induction of apoptosis and paraptosis and inhibition of autophagy in K562 cells

Date Published: May 9, 2018

Publisher: Springer Berlin Heidelberg

Author(s): Haobin Zhao, Lu Yan, Xiaoguang Xu, Chunmei Jiang, Junling Shi, Yawen Zhang, Li Liu, Shuzhen Lei, Dongyan Shao, Qingsheng Huang.


The lipopeptide iturin from Bacillus subtilis has been found to have a potential inhibitory effect on breast cancer, alveolar adenocarcinoma, renal carcinoma, and colon adenocarcinoma. In this study, the potential of B. subtilis lipopeptides (a mixture of iturin homologues, concentration of 42.75%) to inhibit chronic myelogenous leukemia was evaluated using K562 myelogenous leukemia cells. The results showed that the lipopeptides could completely inhibit the growth of K562 at 100 μM, with an IC50 value of 65.76 μM. The lipopeptides inhibited the profile of K562 via three pathways: (1) induction of paraptosis indicated by the occurrence of cytoplasmic vacuoles, and swelling of the mitochondria and endoplasmic reticulum (ER) without membrane blebbing in the presence of a caspase inhibitor; (2) inhibition of autophagy progress illustrated by the upregulated expression of LCII and P62; and (3) induction of apoptosis by causing ROS burst, and induction of the intrinsic pathway indicated by the upregulated expression of cytochrome c (Cyto-c), bax, and bad, together with downregulated expression of Bcl-2. The ROS-dependent apoptosis and caspase-independent paraptosis were verified using the ROS inhibitor and caspase inhibitor, respectively. The extrinsic apoptosis pathway was not involved in the lipopeptide’s effects on K562. Overall, the B. subtilis lipopeptides (consisting of a majority of iturin) exhibited promising potential in inhibiting chronic myelogenous leukemia in vitro via simultaneously causing paraptosis, apoptosis, and inhibition of autophagy.

Partial Text

Chronic myelogenous leukemia (CML), also called chronic myeloid leukemia, is a cancer involving the bone marrow hematopoietic stem cells. It accounts for approximately 15% of adult leukemia (Shi et al. 2016). The typical properties of this disease
are the chromosomal translocation and increased and unregulated growth of predominantly myeloid cells in the bone marrow, as well as the accumulation of these cells in the blood and spleen (Fu et al. 2016). Although stem cell transplantation (SCT) is an efficient method to cure CML, it tends to result in complications. Furthermore, it is very difficult to find a suitable donor for the patient (Kujak and Kolesar 2016). Tyrosine-kinase inhibitor (TKI) is another drug to treat CML and improve the long-term survival rate, greatly reduce pain, and improve the quality of life of patients. However, since it became a prominent anti-cancer drug in 2001, it has been found to be successful in only 5% of cases (Khan and Bixby 2014; Ross and Mgbemena 2014). TKIs can cause some side effects and certain toxicities, and patients may develop drug resistance or relapse due to chromosomal mutations, and these factors have limited its widespread use. Finding other efficient drugs is imperative to improve the cure rate for CML.

This is the first time to reveal the potential application of and the mechanism for iturin group in inhibiting blood cancer caused by K562. Many reports have indicated that Bacillus lipopeptides engage in anti-fungal, anti-bacterial, and anti-virus activities, and multiple therapeutic activities, such as anti-inflammation, anti-cancer, neuroprotective effects, inhibition of platelet aggregation, and immunomodulation therapy of diabetes (Zhao et al. 2017). The anti-cancer activities of Bacillus lipopeptides have been demonstrated with human breast cancer MCF-7 cells (Cao et al. 2010), and the human lung cancer cell line 95D (Yin et al. 2013). The current study is the first report describing the effect of Bacillus lipopeptides on blood cancer caused by K562 leukemia cells and indicates that B. subtilis lipopeptides, mainly the iturin groups, have potential in treating leukemia.




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