Mikio Namiki

The Adrenal Androgen Androstenediol Is Present in Prostate Cancer Tissue after Androgen Deprivation Therapy and Activates Mutated Androgen Receptor

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR’s association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.

The bisphosphonate YM529 inhibits osteolytic and osteoblastic changes and CXCR-4-induced invasion in prostate cancer

Bisphosphonates are useful for the treatment of prostate cancer bone metastasis. However, the role of bisphosphonate on the development of the osteoblastic component of prostate cancer bone metastases is not defined. In the present study, the third-generation bisphosphonate, YM529 (minodoronate), was tested for its effects on the osteolytic PC-3 and novel osteoblastic LNCaP-SF cell lines. YM529 inhibited both osteolytic and osteoblastic changes in an intratibial tumor injection murine model. In vitro, YM529 inhibited both the proliferation and the invasion of both prostate cancer cell lines. The stromal cell-derived factor-1 (or CXCL12)/CXCR-4 pathway is believed to play an important role in the development of prostate cancer bone metastases. Thus, we determined if YM529 affected this pathway. YM529 suppressed CXCR-4 expression in PC-3 and LNCaP-SF in vitro and in vivo and this was associated with decreased in vitro invasion. These results suggest that YM529 may inhibit cancer cell invasion into the bone matrix by repressing the expression of CXCR-4 in bone metastasis lesions.

Novel HER2 selective tyrosine kinase inhibitor, TAK‐165, inhibits bladder, kidney and androgen‐independent prostate cancer in vitro and in vivo

Purpose:u2002 TAK‐165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyrosine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen‐independent prostate cancer. We therefore investigated the antitumor effect of TAK‐165 on these urological cancer cells.

Bisphosphonate induces apoptosis and inhibits pro-osteoclastic gene expression in prostate cancer cells.

Aim:u2002 Bisphosphonates are well established for the management of cancer‐induced skeletal complications. Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To determine the direct effects of bisphosphonate on prostate cancer, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis‐related proteins and osteoclastogenic factors.

CTEN/tensin 4 expression induces sensitivity to paclitaxel in prostate cancer

Recently, we established paclitaxel‐resistant prostate cancer cell lines (PC‐3‐TxR and DU145‐TxR). To determine the mechanisms of paclitaxel resistance in PC‐3‐TxR cells, we compared the gene expression profiles between PC‐3 and PC‐3‐TxR cells. Our results indicated that expression of the C‐terminal tensin like protein (CTEN, tensin 4) gene was down‐regulated by 10‐fold in PC‐3‐TxR cells. We investigated the possibility that CTEN overexpression restores paclitaxel sensitivity.

Establishment and characterization of androgen‐independent human prostate cancer cell lines, LN‐REC4 and LNCaP‐SF, from LNCaP

Aim:u2003 To investigate the mechanisms of androgen‐independent growth in prostate cancer (PCa), we established two PCa cell lines, LN‐REC4 and LNCaP‐SF, from the androgen‐dependent PCa cell line, LNCaP.

Down‐regulation of calcium/calmodulin‐dependent protein kinase kinase 2 by androgen deprivation induces castration‐resistant prostate cancer

Conversion into androgen‐hypersensitive state and adaptation to the low concentration of androgen during ADT cause relapse of prostate cancer (PCa). It is important to identify differentially expressed genes between PCa and normal prostate tissues and to reveal the function of these genes that are involved in progression of PCa.

Cranial nerve deficit caused by skull metastasis of prostate cancer : three Japanese castration-resistant prostate cancer cases

We report 3 Japanese patients with cranial nerve deficit caused by skull metastasis of prostate cancer (PCa). Case 1 was a 75-year-old patient with a chief complaint of diplopia. The cause of diplopia was right oculomotor nerve palsy from the skull metastasis. External beam radiation therapy (EBRT) to the whole brain, 40xa0Gy in 20 fractions, was performed and the diplopia improved. Case 2 was a 72-year-old patient with a chief complaint of facioplegia. Bone scintigraphy and computed tomography (CT) of the head revealed right occipital bone metastasis of PCa resulting in right facial nerve palsy. EBRT to the right occipital bone, 50xa0Gy in 25 fractions, with daily oral dexamethasone (DEX) was performed and facioplegia showed complete recovery. At 12xa0months after onset, the patient was followed-up with no symptoms. Case 3 was a 74-year-old patient with a chief complaint of diplopia. Diffusion-weighted magnetic resonance imaging (MRI) and positron emission tomography (PET) showed right petrous bone metastasis resulting in right abducent nerve palsy. EBRT to the right petrous bone, 44xa0Gy in 22 fractions, with oral DEX was performed and diplopia showed complete recovery. At 13xa0months after onset, the patient was followed-up with no symptoms. MRI and PET may detect PCa metastasis in the skull base more clearly than other imaging modalities. EBRT with 40–50xa0Gy in 20–25 fractions in association with corticosteroid administration may be reasonable treatment of patients with metastatic PCa who develop cranial nerve dysfunction.

Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: implications for clinical practice.

Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer (CRPC) has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen (PSA). However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.

Risedronate prevents persistent bone loss in prostate cancer patients treated with androgen deprivation therapy: results of a 2-year follow-up study

Androgen deprivation therapy (ADT) for prostate cancer (PCa) causes bone loss. Although we reported previously that risedronate significantly recovers bone mineral density (BMD) for up to 12 months, there have been no reports with longer follow-up periods to date. This study extended our earlier series extending the follow-up period to 24 months. Eligible patients had histologically confirmed PCa without lumbar spine metastasis and underwent ADT. Lumbar spine BMD, urinary deoxypyridinoline (uDPD) and serum bone alkaline phosphatase were measured at 6, 12 and 24 months. Among the total of 96 patients, we analyzed 26 and 18 patients in risedronate administration and control groups, respectively. BMD relative to the young adult mean ratio, uDPD and serum bone alkaline phosphatase of the risedronate administration group recovered significantly after 24 months compared with the control group (P<0.0001, P=0.0001, and P<0.0001, respectively). Transient blurred vision, malaise and vertigo were observed in 1 patient each among the 46 patients treated with risedronate within 28 days after first administration. Oral administration of risedronate is safe and effective for the recovery of ADT-induced bone loss in PCa patients even at 24 months after commencement of treatment.