The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells

Abstract

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemo-resistant tumors. The aim of this study is to evaluate the role of Palomid 529 (P529), a novel TORC1/TORC2 inhibitor, in association with docetaxel (DTX) and cisplatin (CP). This work utilizes a wide panel of prostatic cancer cell lines with or without basal activation of Akt as well as two in vivo models of aggressive HRPC. The blockade of Akt/mTOR activity was associated to reduced cell proliferation and induction of apoptosis. Comparison of IC50 values calculated for PTEN-positive and PTEN-negative cell lines as well as the PTEN transfection in PC3 cells or PTEN silencing in DU145 cells revealed that absence of PTEN was indicative for a better activity of the drug. In addition, P529 synergized with DTX and CP. The strongest synergism was achieved when prostate cancer (PCa) cells were sequentially exposed to CP or DTX followed by treatment with P529. Treatment with P529 before the exposure to chemotherapeutic drugs resulted in a moderate synergism, whereas intermediated values of combination index were found when drugs were administered simultaneously. In vivo treatment of a combination of P529 with DTX or CP increased the percentage of complete responses and reduced the number of mice with tumor progression. Our results provide a rationale for combinatorial treatment using conventional chemotherapy and a Akt/mTOR inhibitor as promising therapeutic approach for the treatment of HRPC, a disease largely resistant to conventional therapies.

Differential effects of PXD101 (belinostat) on androgen-dependent and androgen-independent prostate cancer models

“…Experiments were stopped 30 sec/day after the first day of treatment, mice were sacrificed by carbon dioxide inhalation and tumors were removed surgically. Tumor growth delay (TGD) was determined as % TGD = ((T_C)/C)_100, where T and C are the mean times in days required to reach the same fixed tumor volume in the treated group and control group, respectively (24,25). In vivo drug combination studies were evaluated by CalcuSyn [Biosoft, Cambridge, UK).…”

“…For the calculation of CI, the values of cell kill for a fixed tumor volume were considered (determined by the log cell kill (LCK)]. Log cell kill was determined as LCK = (T-C)/ (3.3-Td), where Td represents the mean control group doubling time required to reach a fixed tumor volume, expressed in days, whereas T and C are the same values as described above (24,25).…”

mTOR pathway in colorectal cancer: an update

“…It may inhibit a chaperone, which assembles the mTOR complexes. Nevertheless, P529 was reported to inhibit tumor growth, angiogenesis, and vascular permeability [150], and to be effective in the treatment of prostate cancer [151, 152]. Moreover, P529 was explored as a therapeutic option for the treatment of keloid disease [153].…”

Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo

“…786-O cells (5×10 6 cells per mouse) were inoculated via s.c. injection to the severe combined immunodeficiency (SCID) mice. Tumor growth curve results show that Palomid 529 (100 mg/kg/2 d, i.p., for 18 days) [20,21] administration significantly inhibited 786-O xenograft tumor growth in SCID mice (Fig. 7A).…”