antofine and Lung-Neoplasms

New water soluble antofine C-13a analogues were designed, synthesized, and evaluated for antiproliferative activity against cancer cells. Particularly, (-)-(R)-13a-hydroxymethylantofine ((-)-(R)-4b) demonstrated notable growth inhibition against a panel of human cancer cell lines. This growth inhibition was associated with the arrest of the cell cycle in the G0/G1 phases and suppression of mTOR signaling in human lung A549 cancer cells. Compound (-)-(R)-4b also overcame paclitaxel-resistance in human lung cancer cells (A549-Pa) by suppressing P-glycoprotein expression. Furthermore, compound (-)-(R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model, which suggests it is a promising novel antitumor agent with sufficient aqueous solubility.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; G1 Phase Cell Cycle Checkpoints; HCT116 Cells; HEK293 Cells; Humans; Indoles; Lung Neoplasms; Mice; Mice, Nude; Phenanthrolines; Signal Transduction; Stereoisomerism; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Water

Various E-ring hydroxylated antofine and cryptopleurine analogues were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of nonsmall cell lung cancer (NSCLC) cell lines in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down-regulate HSP90 and β-catenin in A549 lung adenocarcinoma cells in a dose-dependent manner, suggesting a potential use for treating hedgehog pathway-driven tumorigenesis.

Topics: Adenocarcinoma; Alkaloids; Antineoplastic Agents; beta Catenin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Design; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Indoles; Lung Neoplasms; Phenanthrolines; Quinolizidines; Stereoisomerism; Structure-Activity Relationship

Multidrug resistance (MDR) is a major obstacle in effective chemotherapy for cancer patients. The expression of P-glycoprotein (P-gp) in cancer cells is highly correlated with resistance to chemotherapeutic drugs. (-)-Antofine, a phenanthroindolizidine alkaloid derived from Cynanchum paniculatum, inhibits the growth of various human cancer cells. In this study, we further explored the potential of (-)-antofine to overcome the resistance induced by anti-cancer drugs. To this end, we established the paclitaxel-resistant human lung cancer cell line A549-PA by gradually exposing A549 cells to increasing concentrations of paclitaxel. As a result, the A549-PA cells acquired resistance against paclitaxel treatment and had an IC50 that was more than 200 times that of the parental A549 cells. (-)-Antofine, however, effectively suppressed the growth of both the parental and drug-resistant cells. Additional studies revealed that the anti-proliferative activity of (-)-antofine in A549-PA cells is accompanied by a down-regulation of P-gp mRNA and protein expression. The effect of reversing the multidrug resistance of A549-PA cells via (-)-antofine treatment was demonstrated an increase in intracellular rhodamine-123 accumulation, measured using FACS analysis. These findings suggest an additional chemotherapeutic value of (-)-antofine, that is, regulation of cancer cell drug resistance, in addition to its antitumor effect.

Topics: Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Base Sequence; Cell Line, Tumor; Cell Proliferation; DNA Primers; Drug Resistance, Neoplasm; Humans; Indoles; Lung Neoplasms; Paclitaxel; Phenanthrolines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction