Riluzole, a glutamate release inhibitor, has been in use for the treatment of amyotrophic lateral sclerosis for over two decades since its approval by the Food and Drug Administration. Recently, riluzole has been evaluated in cancer cells and indicated to block cell proliferation and/or induce cell death. Riluzole has been proven effective as an anti‑neoplastic drug in cancers of various tissue origins, including the skin, breast, pancreas, colon, liver, bone, brain, lung and nasopharynx. While cancer cells expressing glutamate receptors frequently respond to riluzole treatment, numerous types of cancer cell lacking glutamate receptors unexpectedly responded to riluzole treatment as well. Riluzole was demonstrated to interfere with glutamate secretion, growth signaling pathways, Ca²⁺ homeostasis, glutathione synthesis, reactive oxygen species generation and integrity of DNA, as well as autophagic and apoptotic pathways. Of note, riluzole is highly effective in inducing cell death in cisplatin‑resistant lung cancer cells. Furthermore, riluzole pretreatment sensitizes glioma and melanoma to radiation therapy. In addition, in triple‑negative breast cancer, colorectal cancer, melanoma and glioblastoma, riluzole has synergistic effects in combination with select drugs. In an effort to highlight the therapeutic potential of riluzole, the current study reviewed the effect and outcome of riluzole treatment on numerous cancer types investigated thus far. The mechanism of action and the various molecular pathways affected by riluzole are discussed.

Glioblastomas exploit various molecular pathways to promote glutamate- dependent growth by activating the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptor, the group II metabotropic glutamate receptor, mGluR, and the epidermal growth factor receptor, EGFR. We hypothesized that targeting more than one of these pathways would be more effective in inhibiting glutamate-dependent growth. Using a model of U87 cell line, we show that blocking glutamate release by Riluzole inhibits cell proliferation. Glutamate-dependent growth is effectively inhibited by a combination of Iressa, an inhibitor of EGFR activation and LY341495, a group II mGluR inhibitor. Treatment of U87 cells with a combination of Iressa and LY341495 inhibits proliferation as indicated by Ki-67 staining, induces apoptosis and inhibits migration of U87 cells more effectively than the treatment by Iressa or LY341495 alone. These results demonstrate that a combinatorial therapy with Iressa and LY341495 is more effective due to synergistic effects of these drugs in inhibiting the growth of glioblastoma.

Osteosarcomas are malignant tumors of bone, most commonly seen in children and adolescents. Despite advances in modern medicine, the poor survival rate of metastatic osteosarcoma has not improved in two decades. In the present study we have investigated the effect of Riluzole on a human and mouse metastatic osteosarcoma cells. We show that LM7 cells secrete glutamate in the media and that mGluR5 receptors are required for the proliferation of LM7 cells. Riluzole, which is known to inhibit glutamate release, inhibits proliferation, induces apoptosis and prevents migration of LM7 cells. This is also seen with Fenobam, a specific blocker of mGluR5. We also show that Riluzole alters the phosphorylation status of AKT/P70 S6 kinase, ERK1/2 and JNK1/2. Thus Riluzole is an effective drug to inhibit proliferation and survival of osteosarcoma cells and has therapeutic potential for the treatment of osteosarcoma exhibiting autocrine glutamate signaling.

Osteosarcomas are the most commonly occurring malignant bone cancer in young individuals. The survival rate of patients with metastatic osteosarcoma is low and has been stagnant for over two decades. We previously demonstrated that the glutamate release inhibitor, riluzole inhibits osteosarcoma cell growth. Towards the development of more effective therapy, we investigated the delivery of riluzole in human metastatic osteosarcoma xenografts in mice. We compared the efficacy of riluzole delivery by intraperitoneally injecting either free riluzole or riluzole released via two different shapes of iron oxide nanoparticles (nanocage or nanosphere) of size 15±2.5 nm. We monitored tumor size using Vernier calipers and bioluminescence assay and found a significant reduction in tumor size in the riluzole‑treated groups when injected, either in free form or via nanoparticles, compared to the control groups (PBS, nanosphere or nanocage). Importantly, nanocage‑delivered riluzole was most effective in reducing tumor size in the xenograft nude mice. While riluzole delivery induced apoptosis in tumor tissues in all three groups of riluzole‑treated animals, it was highest in tumors from the nanocage‑delivered riluzole group. Therefore, we conclude that riluzole is an effective drug to reduce tumor size in osteosarcoma and the efficacy of riluzole as a apoptotic and tumor‑reducing drug is enhanced when delivered via nanocage.