Mycophenolic acid is a drug with the potential to be repurposed for suppressing tumor growth and metastasis in osteosarcoma treatment

Abstract

Our previous review of proteomics data showed that in osteosarcoma, some overexpressed proteins were targets of FDAapproved immunosuppressive and anti-arrhythmic drugs, including mycophenolate mofetil (MMF), ribavirin, leflunomide, azathioprine and digoxin. Here, these drugs were screened for growth inhibitory effects in human osteosarcoma cell lines, including MNNG/HOS, U2OS, SaOS-2, MG-63 and 143B cells. Only mycophenolic acid (MPA), an active metabolite of MMF, efficiently inhibited osteosarcoma cell growth with IC 50 values of 0.46-7.3 μM; these values are in the therapeutic range for organ transplant patients. At a therapeutic dose (10 μM), MPA significantly inhibited colony formation, caused cell cycle arrest in the S phase, and induced apoptosis. Moreover, the in vitro invasion of osteosarcoma cells was reduced by MPA by inhibiting cell migration capability. The in vivo antitumor effect of MMF was determined in nude mice harboring 143B cell xenografts. Daily oral administration of 200 mg/kg/day MMF for 2 weeks significantly suppressed tumor growth in treated mice, achieving 57.4 AE 11.1% tumor growth inhibition. Compared with the vehicle group, the MMF group treated with 50-200 mg/kg/day for 3 weeks had a significant reduction in the number of lung metastatic nodules in a tail vein-lung metastasis model of 143B cells. MMF doses of 50, 100 and 200 mg/kg/day are approximately equivalent to the non-toxic doses of 0.25, 0.5 and 1 g/day in humans, respectively. These findings indicate that MPA/MMF can effectively control osteosarcoma tumor growth and metastasis. Thus, the potential to repurpose MPA/MMF for use in osteosarcoma chemotherapy is of great interest.Additional Supporting Information may be found in the online version of this article.

Transient NK Cell Depletion Facilitates Pulmonary Osteosarcoma Metastases After Intravenous Inoculation in Athymic Mice

“…We next investigated whether transient NK cell depletion increased the efficiency with which intravenous inoculation of 143B human osteosarcoma cells produced lung metastases. As mentioned earlier, previous research established that these cells could form lung metastases after intravenous injection, [5][6][7][8][9] but 1-2 million cells were injected in those studies, implying that seeding to the lungs was very inefficient. As with the KRIB cells, tail vein injections of 150,000 luciferase-tagged 143B cells failed to yield lung metastases (Fig.…”

“…To our knowledge, only one human osteosarcoma cell line, 143B, has been used by multiple groups to induce so-called ''experimental metastasis.'' [5][6][7][8][9] Those studies involved injection of at least one million cells to achieve lung metastases. The dearth of examples of osteosarcoma cell lines published to form metastases after intravenous injection, coupled with the large number of 143B cells required to achieve this, implies that the process by which human osteosarcoma cells move from the blood to the lungs in nude mice is extremely inefficient.…”

Phase II, multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Mycophenolate Mofetil in patients with high-grade locally advanced or metastatic osteosarcoma (ESMMO): rationale and design of the ESMMO trial

“…The initial dose of mycophenolate mofetil at 5 g/day which is planned to be used in this phase II clinical trial is based on the pharmacologically active dose in mice, from which human equivalent dose is then calculated, as well as clinically experienced doses in humans. Tumor growth inhibition was evident in mice treated with mycophenolate mofetil at 200 mg/kg/day [18], so mycophenolate mofetil at the dose of 1 g/day or more is expected to be pharmacologically active in humans. In clinical practice, longterm treatment with mycophenolate mofetil at the dose of 2 to 3 g/day has a satisfactory safety profile in organ transplant recipients [47,48].…”

“…In 2010, Fellenberg et al reported the observed overexpression of IMPDH in metastatic and chemo-resistant osteosarcoma cell lines, and pharmacological inhibition of IMPDH could result in a reduction of cell viability and cell proliferation [17]. A recent in vitro study has revealed the anticancer activity of MPA against osteosarcoma cell lines, with the half maximal inhibitory concentration (IC 50 ) of 0.46-7.30 μM across all tested cell lines [18]. The in vivo experiment has shown the inhibition of tumor growth and lung metastasis of osteosarcoma in mice treated with mycophenolate mofetil [18].…”

“…A recent in vitro study has revealed the anticancer activity of MPA against osteosarcoma cell lines, with the half maximal inhibitory concentration (IC 50 ) of 0.46-7.30 μM across all tested cell lines [18]. The in vivo experiment has shown the inhibition of tumor growth and lung metastasis of osteosarcoma in mice treated with mycophenolate mofetil [18]. As a result, mycophenolate mofetil has been recently proposed to be a promising new drug candidate for the treatment of osteosarcoma [19].…”