Down-regulation of the nuclear factor-κB by lidamycin in association with inducing apoptosis in human pancreatic cancer cells and inhibiting xenograft growth

Abstract

Abstract. Pancreatic cancer is now one of the most common causes of cancer death worldwide. K-ras mutations are present in up to 90% of pancreatic cancer cases. The expression of mutant K-ras activates the Akt/protein kinase B pathway, resulting in the activation of the nuclear factor-κB (NF-κB) transcriptional factor. Constitutive NF-κB activity plays a key role in pancreatic carcinoma. NF-κB has been shown to inhibit apoptosis in response to chemotherapeutic agents. In the present study, the effects of lidamycin (LDM), a member of the enediyne antibiotic family, were investigated on two established pancreatic cell lines, PANC-1 and SW1990. A dose-dependent inhibition of phospho-Akt and NF-κB activation was found in the cells treated with LDM as determined by Western blot analysis. Moreover, a downregulation of K-ras mRNA and a protein expression by LDM were observed in both cell lines as determined by reverse transcription-PCR and Western blot analysis. By MTT assay, a remarkable difference in chemosensitivity to LDM, mitomycin, adriamycin, taxol, and gemcitabine was found in both cell lines. The IC 50 values of LDM for the PANC-1 or SW1990 cells were 0.955±0.414 or 0.426±0.212 nM, respectively, lower than those of the other drugs. Growth inhibition, apoptosis induction and cell cycle arrest were observed in the LDMtreated cells. LDM decreased the invasive potential of pancreatic cancer cells by reducing matrix metalloproteinase-9 activity. Furthermore, LDM was found to suppress the growth of SW1990 xenografts in nude mice. Treatment with an i.v. injection of LDM at the dose of 0.02 and 0.04 mg/kg (once a week for two weeks) inhibited the growth of xenografts by 66 and 72%, respectively. By contrast, an i.p. injection of gemcitabine at the dose of 80 mg/kg inhibited the growth of xenografts by 38%. Our findings suggest that LDM is active in the down-regulation of NF-κB and could play a positive role in relevant targeted chemotherapy for pancreatic carcinoma.

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

“…The transcription nF-κB has been linked to cell proliferation, invasion, angiogenesis, metastasis and the suppression of apoptosis in pancreatic cancer (13)(14)(15)(16). Many conventional cancer chemotherapeutic agents, such as gemcitabine, vinblastine, vincristine, daunomycin, doxorubicin, campothecin, cisplatin and etoposide, have been shown to activate nF-κB (13,14,16,17).…”

“…nF-κB promotes pancreatic cancer growth via the inhibition of apoptosis (18,20). additionally, nF-κB-regulated gene products promote the migration and invasion of cancer cells (15), and nF-κB may play a pivotal role in promoting gemcitabine resistance in pancreatic cancer (21). These findings implicate NF-κB in pancreatic cancer, and suggest that agents blocking nF-κB activation may reduce chemoresistance to gemcitabine and perhaps be used in combination with gemcitabine as a novel therapeutic regimen for pancreatic cancer.…”

Lidamycin shows highly potent cytotoxic to myeloma cells and inhibits tumor growth in mice

“…It is well known that DSB is the most severe DNA lesion, which may explain the highly potent cytotoxicity of LDM toward cancer cells. LDM shows extremely potent cytotoxicity, anti-angiogenic activity and a marked inhibition of transplantable tumors in mice [9][10][11] . The LDM molecule contains an enediyne chromophore (M r 843 Da) responsible for the extremely potent bioactivity and a noncovalently bound apoprotein (M r 10.5 kDa), which forms a hydrophobic pocket for protecting the chromophore [12] .…”

Lidamycin inhibits tumor growth and pulmonary metastasis in murine breast carcinoma and shows synergy with paclitaxel

“…As an enediyne anticancer antibiotic, LDM showed extremely potent cytotoxicity toward cultured cancer cells and markedly inhibited the growth of transplantable tumors in mice [30][31][32]. LDM (C1027) also showed antiangiogenesis and antimetastatic activity, preferentially targeting hypoxic cells [14].…”