Abstract
Isocorydine (ICD), an anticancer agent under current evaluation, decreased the percentage of side population (SP) cells significantly in hepatocellular carcinoma (HCC) cell lines. ICD treatment sensitized cancer cells to doxorubicin (DXR), a conventional clinical chemotherapeutic drug for HCC. We found that ICD decreased the percentage of SP cells in HCC cell lines by preferentially killing SP cells. In the early stage of treatment, ICD inhibited SP cell growth by arresting cells in G2/M; later, it induced apoptosis. Our xenograft model confirmed that ICD selectively reduced the size and weight of SP-induced tumor masses in vivo. Furthermore, it was found that programmed cell death 4 (PDCD4), a tumor suppressor gene, was relatively low when expressed in SP cells compared with non-SP cells, and its expression level was remarkably elevated when cells were treated with ICD. Taken together, these data suggest that ICD is a drug that may target the SP cells of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer mortality worldwide, resulting in 600,000 deaths annually [1]
Using cDNA microarray, we found that programmed cell death 4 (PDCD4) was upregulated in HCC cell lines treated with ICD; we confirmed this upregulation by Western blot
We found that ICD significantly decreased the fraction of side population (SP) cells in the PLC/PRF/5, MHCC-97L, SNU449, MHCC-97H and MHCC-LM3 cell lines in both time-dependent and dosedependent manners
Summary
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer mortality worldwide, resulting in 600,000 deaths annually [1]. Resistance to conventional chemotherapy is acknowledged as a major obstacle for the effective treatment of cancer. There are multiple reasons for the drug resistance of HCC, among which is overproduction of some ATPbinding cassette (ABC)-dependent transporter family members [2]. ATP-binding cassette-dependent subfamily G member 2 (ABCG2) is an important member of this family that correlates with drug resistance. This transporter can efflux many conventional drugs out of cancer cells, rendering chemotherapy ineffective. ABCG2 expression is known to be essential for the side population (SP) phenotype [3]
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