Novel Curcumin-Resveratrol Solid Nanoparticles Synergistically Inhibit Proliferation of Melanoma Cells.

Polyphenols such as curcumin (Cur) and resveratrol (Res) have been recently shown to have potential to inhibit proliferation of highly aggressive melanoma cells. This study was designed to investigate the feasibility of a topical delivery system, using a solid lipid nanoparticles (SLNs) loaded delivery systems, that can enhance the skin penetration and anti-cancer efficacy of combination of these polyphenols. Negatively charged Cur-Res SLNs with a mean diameter of 180.2 ± 7.7 nm were prepared using high shear homogenization method. Cur-Res SLNs were found to be stable up to 2 weeks under 4°C. The in vitro release study showed that Res was released five time more than curcumin. The permeability of resveratrol was about 1.67 times that of curcumin from the SLN-gel formulation which was significantly (p < 0.05) lower than from SLN suspension. More than 70% of Cur-Res SLNs were bound to skin locally in a skin binding study suggesting potentially utility of Cur-Res SLNs in the treatment of localized melanoma. In fact, the electrical cell-substrate impedance sensing (ECIS) measurements suggested that Cur-Res combination has potential to stop cell migration of B16F10 melanoma cells. Furthermore, both, Cur-Res SLNs and Cur-Res solution at the ratio of 3:1 demonstrated a strong synergistic inhibition of SK-MEL-28 melanoma cell proliferation. Further evaluation of Cur-Res SLNs in vivo melanoma models are warranted to establish the clinical utility of Cur-Res formulations in melanoma therapy.

Chemotherapy impedes in vitro microcirculation and promotes migration of leukemic cells with impact on metastasis.

Although most cancer drugs target the proliferation of cancer cells, it is metastasis, the complex process by which cancer cells spread from the primary tumor to other tissues and organs of the body where they form new tumors, that leads to over 90% of all cancer deaths. Thus, there is an urgent need for anti-metastasis therapy. Surprisingly, emerging evidence suggests that certain anti-cancer drugs such as paclitaxel and doxorubicin can actually promote metastasis, but the mechanism(s) behind their pro-metastatic effects are still unclear. Here, we use a microfluidic microcirculation mimetic (MMM) platform which mimics the capillary constrictions of the pulmonary and peripheral microcirculation, to determine if in-vivo-like mechanical stimuli can evoke different responses from cells subjected to various cancer drugs. In particular, we show that leukemic cancer cells treated with doxorubicin and daunorubicin, commonly used anti-cancer drugs, have over 100% longer transit times through the device, compared to untreated leukemic cells. Such delays in the microcirculation are known to promote extravasation of cells, a key step in the metastatic cascade. Furthermore, we report a significant (p < 0.01) increase in the chemotactic migration of the doxorubicin treated leukemic cells. Both enhanced retention in the microcirculation and enhanced migration following chemotherapy, are pro-metastatic effects which can serve as new targets for anti-metastatic drugs.

In vitro radiotherapy and chemotherapy alter migration of brain cancer cells before cell death.

Although radiotherapy and most cancer drugs target the proliferation of cancer cells, it is metastasis, the complex process by which cancer cells spread from the primary tumor to other tissues and organs of the body where they form new tumors, that leads to over 90% of all cancer deaths. Thus, there is an urgent need for anti-metastasis strategies alongside chemotherapy and radiotherapy. An important step in the metastatic cascade is migration. It is the first step in metastasis via local invasion. Here we address the question whether ionizing radiation and/or chemotherapy might inadvertently promote metastasis and/or invasiveness by enhancing cell migration. We used a standard laboratory irradiator, Faxitron CellRad, to irradiate both non-cancer (HCN2 neurons) and cancer cells (T98G glioblastoma) with 2 Gy, 10 Gy and 20 Gy of X-rays. Paclitaxel (5 µM) was used for chemotherapy. We then measured the attachment and migration of the cells using an electric cell substrate impedance sensing device. Both the irradiated HCN2 cells and T98G cells showed significantly (p < 0.01) enhanced migration compared to non-irradiated cells, within the first 20-40 h following irradiation with 20 Gy. Our results suggest that cell migration should be a therapeutic target in anti-metastasis/anti-invasion strategies for improved radiotherapy and chemotherapy outcomes.

Microgravity Modulates Effects of Chemotherapeutic Drugs on Cancer Cell Migration.

Microgravity or the condition of apparent weightlessness causes bone, muscular and immune system dysfunctions in astronauts following spaceflights. These organ and system-level dysfunctions correlate with changes induced at the single cell level both by simulated microgravity on earth as well as microgravity conditions in outer space (as in the international space station). Reported changes in single bone cells, muscle cells and white blood cells include structural/morphological abnormalities, changes in gene expression, protein expression, metabolic pathways and signaling pathways, suggesting that cells mount some response or adjustment to microgravity. However, the implications of such adjustments on many cellular functions and responses are not clear largely because the primary mechanism of gravity sensing in animal cells is unknown. Here, we used a rotary cell culture system developed by NASA to subject leukemic and erythroleukemic cancer cells to microgravity for 48 h and then quantified their innate immune response to common anti-cancer drugs using biophysical parameters and our recently developed quantum-dot-based fluorescence spectroscopy. We found that leukemic cancer cells treated with daunorubicin show increased chemotactic migration (p < 0.01) following simulated microgravity (µg) compared to normal gravity on earth (1 g). However, cells treated with doxorubicin showed enhanced migration both in 1 g and following µg. Our results show that microgravity modulates cancer cell response to chemotherapy in a drug-dependent manner. These results suggest using simulated microgravity as an immunomodulatory tool for the development of new immunotherapies for both space and terrestrial medicine.