Heteronemin, a marine natural product, sensitizes acute myeloid leukemia cells towards cytarabine chemotherapy by regulating farnesylation of Ras.

Cytarabine is a conventionally used chemotherapeutic agent for treating acute myeloid leukemia (AML). However, chemoresistance, toxic side-effects and poor patient survival rates retard the efficacy of its performance. The current study deals with the chemosensitization of AML cells using heteronemin, a marine natural product towards cytarabine chemotherapy. Heteronemin could effectively sensitize HL-60 cells towards sub-toxic concentration of cytarabine resulting in synergistic toxicity as demonstrated by MTT assay and [3H] thymidine incorporation studies, while being safe towards healthy blood cells. Flow cytometry for Annexin-V/PI and immunoblotting for caspase cleavage proved that the combination induces enhancement in apoptosis. Heteronemin being a farnesyl transferase inhibitor (FTI) suppressed cytarabine-induced, farnesyl transferase-mediated activation of Ras, as assessed by Ras pull-down assay. Upon pre-treating cells with a commercial FTI, L-744,832, the synergism was completely lost in the combination, confirming the farnesyl transferase inhibitory activity of heteronemin as assessed by thymidine incorporation assay. Heteronemin effectively down-regulated cytarabine-induced activation of MAPK, AP-1, NF-κB and c-myc, the down-stream targets of Ras signaling, which again validated the role of Ras in regulating the synergism. Hence we believe that the efficacy of cytarabine chemotherapy can be improved to a significant extent by combining sub-toxic concentrations of cytarabine and heteronemin.

Folic acid conjugation improves the bioavailability and chemosensitizing efficacy of curcumin-encapsulated PLGA-PEG nanoparticles towards paclitaxel chemotherapy.

Nanoencapsulation has emerged as a novel strategy to enhance the pharmacokinetic and therapeutic potential of conventional drugs. Recent studies from our lab have established the efficacy of curcumin in sensitizing cervical cancer cells and breast cancer cells towards paclitaxel and 5-FU chemotherapy respectively. Factors that hinder the clinical use of curcumin as a sensitizer or therapeutic agent include its poor bioavailability and retention time. Earlier reports of improvement in bioavailability and retention of drugs upon nanoencapsulation have motivated us in developing various nanoformulations of curcumin, which were found to exhibit significant enhancement in bioavailability and retention time as assessed by our previous in vitro studies. Among the various formulations tested, curcumin-entrapped in PLGA-PEG nanoparticles conjugated to folic acid (PPF-curcumin) displayed maximum cell death. In the present study, we have demonstrated the efficacy of this formulation in augmenting the bioavailability and retention time of curcumin, in vivo, in Swiss albino mice. Further, the acute and chronic toxicity studies proved that the formulation is pharmacologically safe. We have also evaluated its potential in chemosensitizing cervical cancer cells to paclitaxel and have verified the results using cervical cancer xenograft model in NOD-SCID mice. Folic acid conjugation significantly enhanced the efficacy of curcumin in down-regulating various survival signals induced by paclitaxel in cervical cancer cells and have considerably improved its potential in inhibiting the tumor growth of cervical cancer xenografts. The non-toxic nature coupled with improved chemosensitization potential makes PPF-curcumin a promising candidate formulation for clinical trials.

Curcumin inhibits B[a]PDE-induced procarcinogenic signals in lung cancer cells, and curbs B[a]P-induced mutagenesis and lung carcinogenesis.

Benzo[a]pyrene is a procarcinogen present in environment and cigarette smoke, which could be bio-transformed in vivo to B[a]PDE, a potent carcinogen known to form DNA adducts and induce mutations. We observed that curcumin, a known chemopreventive, could significantly inhibit the survival of lung cancer cells exposed to B[a]PDE. It also downregulates B[a]PDE-induced nuclear translocation of NF-κB as assessed by Electrophoretic Mobility Shift Assay (EMSA) and NF-κB-dependent reporter gene assay. Ames assay demonstrated its ability to revert the mutagenic property of benzo[a]pyrene. These observations prompted us to evaluate the efficacy of curcumin in preventing B[a]P-induced lung carcinogenesis in vivo and to explore the molecular mechanism associated with it. The average number of tumor nodules present in the lungs of the Swiss albino mice, which received benzo[a]pyrene, was significantly high compared to that received curcumin as 2% diet along with B[a]P. Curcumin treatment significantly reverted histopathological deviations in the lung tissues due to benzo[a]pyrene ingestion. Moreover, curcumin diet reduced benzo[a]pyrene-induced activation of NF-κB and MAPK signaling and Cox-2 transcription in lung tissues of mice. Taken together, this study illustrates multifaceted efficacy of curcumin in preventing lung cancer.