Abstract
Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2.
Highlights
Lung cancer is the second most common cancer in men and women, and is the leading cause of mortality from cancer [1]
H460 lung cancer cells are extremely sensitive to 10 nM paclitaxel and 100 nM doxorubicin (Figure 1A-1C)
We found that expression of antiapoptotic B-cell lymphoma 2 (Bcl-2) was increased in the H460 resistant cancer cells, which may contribute towards paclitaxel resistance (Figure 2A)
Summary
Lung cancer is the second most common cancer in men and women, and is the leading cause of mortality from cancer [1]. Chemotherapeutic options are critical for the treatment of advanced lung cancer. Taxanes such as paclitaxel are antimitotic agents currently used as standard of care first line therapy either alone, or in combination with platinum-based agents for both primary and advanced lung cancer [3, 4]. Acquired resistance to paclitaxel is common, which is associated with poor prognosis, and limited therapeutic options once resistance occurs [7, 8]. Doxorubicin is another chemotherapeutic which is used for treatment of recurrent small cell lung cancer (SCLC) and resistance to doxorubicin has been reported [9, 10]. It is critical to identify molecular targets and novel approaches to selectively induce death in paclitaxel resistant cancer cells
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