Peer Review #1 of "Relationship between triterpenoid anticancer drug resistance, autophagy, and caspase-1 in adult T-cell leukemia (v0.2)"

We previously reported that the inflammasome inhibitor cucurbitacin D (CuD) induces apoptosis in human leukemia cell lines. Here, we investigated the effects of CuD and a B-cell lymphoma extra-large (Bcl-xL) inhibitor on autophagy in peripheral blood lymphocytes (PBL) isolated from adult T-cell leukemia (ATL) patients. CuD induced PBL cell death in patients but not in healthy donors. This effect was not significantly inhibited by treatment with rapamycin or 3-methyladenine (3-MA). The Bcl-xL inhibitor Z36 induced death in primary cells from ATL patients including that induced by CuD treatment, effects that were partly inhibited by 3-MA. Similarly, cell death induced by the steroid prednisolone was enhanced in the presence of Z36. A western blot analysis revealed that Z36 also promoted CuD-induced poly(ADP ribose) polymerase cleavage. Interestingly, the effects of CuD and Z36 were attenuated in primary ATL patient cells obtained upon recurrence after umbilical cord blood transplantation, as compared to those obtained before chemotherapy. Furthermore, cells from this patient expressed a high level of caspase-1, and treatment with caspase-1 inhibitor-enhanced CuD-induced cell death. Taken together, these results suggest that rescue from resistance to steroid drugs can enhance chemotherapy, and that caspase-1 is a good marker for drug resistance in ATL patients.

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Expression of functional lung resistance–related protein predicts poor outcome in adult T-cell leukemia

Blood ◽

10.1182/blood.v98.4.1160 ◽

2001 ◽

Vol 98 (4) ◽

pp. 1160-1165 ◽

Cited By ~ 49

Author(s):

Nobuhito Ohno ◽

Ayako Tani ◽

Kimiharu Uozumi ◽

Shuichi Hanada ◽

Tatsuhiko Furukawa ◽

...

Keyword(s):

Drug Resistance ◽

T Cell ◽

T Cell Leukemia ◽

Related Protein ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Poor Outcome ◽

Cell Counts ◽

Lung Resistance ◽

Lymphoma Type

Chemotherapy of patients with adult T-cell leukemia (ATL) has been unsuccessful. The poor outcome is thought to be caused mainly by the drug resistance of ATL cells. Lung resistance–related protein (LRP) is a novel protein associated with drug resistance. The expression of LRP messenger RNA (mRNA) was evaluated by slot blot analysis in 55 patients with ATL. Of these patients, 36 had acute, 12 chronic, and 7 lymphoma-type ATL. The expression levels of LRP mRNA were significantly higher in chronic ATL than in lymphoma-type ATL (P = .007). The expression of LRP mRNA was higher in patients with white blood cell counts above 30 000/μL (P = .038) or with abnormal lymphocyte counts above 10 000/μL (P = .007) than in the remaining patients. The enhanced efflux of [14C]doxorubicin from nuclei isolated from ATL cells that expressed high levels of LRP was inhibited by a polyclonal antibody against LRP, and the accumulation of doxorubicin in the isolated nuclei was increased by the anti-LRP antibody. In acute and lymphoma-type ATL patients, high expression of LRP mRNA at diagnosis correlated with shorter survival, and a Cox proportional hazards model showed that LRP expression is an independent prognostic factor. These findings suggest that functionally active LRP is expressed in some ATL cells and that it is involved in drug resistance and poor prognosis in ATL.

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Possible Roles of an Adult T-Cell Leukemia (ATL)-Derived Factor/Thioredoxin in the Drug Resistance of ATL to Adriamycin

Blood ◽

10.1182/blood.v89.7.2480 ◽

1997 ◽

Vol 89 (7) ◽

pp. 2480-2487 ◽

Cited By ~ 45

Author(s):

Jingxin Wang ◽

Masanobu Kobayashi ◽

Keisuke Sakurada ◽

Masahiro Imamura ◽

Tetsuya Moriuchi ◽

...

Keyword(s):

Drug Resistance ◽

T Cell ◽

Cell Lines ◽

Topoisomerase Ii ◽

Leukemia Cell ◽

Lymphocytic Leukemia ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Leukemia Cell Lines

Abstract Chemotherapy for adult T-cell leukemia (ATL) has been reported to fail to induce complete remission because of drug resistance in most patients. We have examined the expression of an ATL-derived factor (ADF)/thioredoxin in relation to resistance to adriamycin (ADM) in various T-cell leukemia cell lines including ATL cell lines. Immunoblot analysis demonstrated that ATL cell lines expressed ADF/thioredoxin at levels 2.8 to 12 times those of other T-cell acute lymphocytic leukemia (T-ALL) cell lines, and that ATL cell lines were 2 to 15 times more resistant to ADM than other T-ALL cell lines. Therefore, we established ADM-resistant cell lines from three different ATL cell lines, and examined the correlation between ADM resistance and expression of ADF/thioredoxin. ADM-resistant ATL cell lines were also found to be resistant to other drugs such as cisplatin and etoposide, and they expressed ADF/thioredoxin at levels 5 to 10 times those of parent ATL cell lines. Diamide and sodium selenite, which have been reported to inhibit ADF/thioredoxin, restored the sensitivity to ADM in ATL and ADM-resistant ATL cell lines. The MDR-1 gene product, a membrane P-glycoprotein (Pgp), was not expressed on ATL cell lines or ADM-resistant ATL cell lines. Topoisomerase II and glutathione peroxidase activities in T-cell leukemia cell lines were not correlated with ADM resistance. These results suggest that ADF/thioredoxin may play an important role in the drug resistance of ATL cells to ADM.

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