Enhanced Antitumor Therapy by Inhibition of p21waf1 in Human Malignant Mesothelioma

Abstract

Purpose: The p21 cyclin-dependent kinase inhibitor was frequently expressed in human malignant pleural mesothelioma (MPM) tissues as well as cell lines. Recent data indicate that p21keeps tumor cells alive after DNA damage, favoring a survival advantage. In this study, we assessed the possibility of p21suppression as a therapeutic target for MPM. Experimental Design: We established two different MPM-derived (from H28 and H2052 cells) subclones using vector-based short hairpin RNA (shRNA). Then, chemosensitivity against low doses of antineoplastic DNA-damaging agents was investigated by colony formation assays, and furthermore, the type of cell response induced by these drugs was analyzed. To examine the effect of p21shRNA on chemosensitivity in vivo, tumor formation assays in nude mice were done. Results: In colony formation assay, the IC 50 of doxorubicin was 33 F 3.0 nmol/L in p21 shRNA-transfected cells with respect to 125 F 10 nmol/L of control vector^transfected cells. This enhancement of growth inhibition was achieved by converting a senescence-like growth arrest to apoptosis in response to doxorubicin, etoposide, and CPT11. In the in vivo assays, CPT11 and loss-of-expression of p21 in combination led to considerable suppression of tumor growth associated with a substantially enhanced apoptotic response, whereas CPT11alone was ineffective at inducing these responses. Conclusions:These results indicated that p21might play an important role in chemosensitivity to anticancer agents, and the suppression of its expression might be a potential therapeutic target for MPM.

Role of p21 as a determinant of 1,6-Bis[4-(4-amino-3-hydroxyphenoxy)phenyl] diamantane response in human HCT-116 colon carcinoma cells

“…Our functional studies identified that DPD inhibits cancer cell migration and tumor growth through p21 activation by a p53-independent pathway. These results were consistent with other reports and support the notion that p21 has a crucial role in anticancer therapy (29,30).…”

shRNA-mediated Bmi-1 silencing sensitizes multiple myeloma cells to bortezomib

“…Therefore, the accumulation of p21 may be involved in, but is not absolutely required for, the induction of apoptosis. However, p21, a cyclin-dependent kinase inhibitor, can induce growth arrest by inhibiting cyclin-dependent kinases that drive cell cycle progression, sensitizing cancer cells to chemotherapy (36). The Bcl-2 family is comprised of structurally related proteins that can either inhibit (i.e., Bcl-2) or promote (i.e., Bax) cell death (37).…”

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

“…20,24,25 In addition, the induction of p21 WAF1 that occurs after exposure to various cytotoxic stimuli can inhibit the apoptosis process in malignant hematopoietic cells [26][27][28] and solid tumor cells. 5,29 In the clinical setting, elevated p21 WAF1 expression has been associated with chemotherapy resistance and poor prognosis in acute myeloid leukemia, 30,31 while an association with p21 WAF1 induction and poor clinical outcome in ALL has been proposed. 32 Mechanisms proposed to explain the anti-apoptotic role of p21 WAF1 include transcriptional regulation of anti-apoptotic genes, 33 inhibition of CDKs that are involved in activation of caspases integral to apoptosis downstream of mitochondrial disruption, 9 or direct inhibition of pro-apoptotic proteins, such as procaspase-3, caspase-8 or apoptosis signal-regulating kinase 1.…”