Resistance to growth inhibitory and apoptotic effects of phorbol ester and UCN-01 in aggressive cancer cell lines

Blagosklonny, Mikhail V.; Dixon, Shannon C.; Robey, Robert W.; Figg, William D.

doi:10.3892/ijo.18.4.697

Cited by 19 publications

(19 citation statements)

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“…We took advantage from a well characterized panel of prostate cancer cell lines. [30][31][32] Among prostate cancer cell lines, LNCaP cells are very sensitive to p21, whereas PC3M cells are extremely resistant. 31,32 In LNCaP cells, 50 nM flavopiridol diminished the cytotoxicity of PTX, whereas higher concentrations of flavopiridol were cytotoxic by themselves (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Blagosklonny¹,

Darzynkiewicz²,

Figg³

2002

Cancer Biology & Therapy

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Resting cells are relatively resistant to microtubule-active drugs including paclitaxel (PTX). By causing p53-mediated arrest, pretreatment with low concentrations of doxorubicin (DOX) protected HCT116 cells from the cytotoxicity caused by PTX. Unlike DOX, flavopiridol (FL) did not protect HCT116 cells. Low concentrations of FL (50 nM) induced p21 but not p53. High concentrations of FL (500 nM) decreased levels of p21 and Mdm-2 but dramatically induced p53. Thus, FL reciprocally affects p21 and p53. In LNCaP, a prostate cancer cell line which is highly sensitive to p21-induced growth arrest (p21-sensitive), low concentrations of FL (50 nM) induced p21 (without induction of p53) and caused G1 and G2 arrest. This precluded mitotic arrest, Bcl-2 and Raf-1 phosphorylation, and diminished cell death caused by PTX. In contrast, FL did not protect PC3M, arrest-resitant and highly aggressive prostate cancer cells. Like LNCaP, HL60 and SKBr3 cells are known to be p21-sensitive. As predicted, low concentrations of FL antagonized PTX-mediated cytotoxicity in HL60 and SKBr3 cell lines. In summary, only low concentrations of FL can induce p21, and, in turn, only p21-sensitive cells are protected from PTX.

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Section: Resultsmentioning

confidence: 99%

“…Unlike LNCaP prostate cancer cells, PC3M are highly resistant to p21 and p21-inducing agents such as phorbol ester. [30][31][32] Most importantly, FL and DNA damaging drugs induce p21 by different mechanisms. DNA damaging drugs induce wt p53 which in turn induce p21 (p53-dependent manner).…”

Section: Discussionmentioning

confidence: 99%

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Blagosklonny¹,

Darzynkiewicz²,

Figg³

2002

Cancer Biology & Therapy

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“…In comparison, in normal prostate epithelial cells and endothelial cells, IC50 of UCN-01 as low as 25-35 nM. 57,58 Like normal prostate cells, normal mammary epithelial cells are very sensitive to UCN-01 with an IC50 of 10 nM. UCN-01 inhibits proliferation of endothelial cells at lower concentrations than those that inhibit prostate cancer cells.…”

Section: Inhibitors Of Mitogenic Kinases and Autonomous Growthmentioning

confidence: 99%

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Blagosklonny¹,

Darżynkiewicz²

2002

Cell Cycle

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Avoidance of apoptosis and mitogen-independent growth are hallmarks of cancer. Mitogen-activated kinases (for example, ErbB1, Raf-1, MEK, PI-3-K, mTOR) can suppress chemotherapy-induced apoptosis in cancer cells. While kinase inhibitors restore susceptibility of cancer cells to apoptosis, they do not necessarily cause growth arrest in cancer cells harboring additional mutations in downstream signaling pathways such as inactivation of Rb and overexpression of c-myc. This article provides a conceptual basis for a novel use of inhibitors of mitogenic kinases. While arresting growth of normal cells, kinase inhibitors may not arrest cancer cells but instead can sensitize them to apoptosis. Following pretreatment with low doses of kinase inhibitors, the chemotherapy that predominantly induces apoptosis in cycling cells (cyclotherapy) will kill cancer cells while sparing normal cells.

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“…For example, the TPA tumor promoter is cytostatic in certain normal cells. [59][60][61] Loss of Rb, overexpression of c-myc, and other oncogenic changes can render cells resistant to TPA. 62 Then, TPA inhibits normal epithelial cells but their malignant counterparts, selectively favoring their proliferation.…”

Section: Two Types Of Resistance To Cytotoxic Agentsmentioning

confidence: 99%

Carcinogenesis, cancer therapy and chemoprevention

Blagosklonny

2005

Cell Death Differ

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Carcinogenesis and cancer therapy are two sides of the same coin, such that the same cytotoxic agent can cause cancer and be used to treat cancer. This review links carcinogenesis, chemoprevention and cancer therapy in one process driven by cytotoxic agents (carcinoagents) that select either for or against cells with oncogenic alterations. By unifying therapy and cancer promotion and by distinguishing nononcogenic and oncogenic mechanisms of resistance, I discuss anticancer-and chemopreventive agent-induced carcinogenesis and tumor progression and, vice versa, carcinogens as anticancer drugs, anticancer drugs as chemopreventive agents and exploiting oncogene-addiction and drug resistance for chemoprevention and cancer therapy.

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Resistance to growth inhibitory and apoptotic effects of phorbol ester and UCN-01 in aggressive cancer cell lines

Cited by 19 publications

References 0 publications

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Carcinogenesis, cancer therapy and chemoprevention

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Resistance to growth inhibitory and apoptotic effects of phorbol ester and UCN-01 in aggressive cancer cell lines

Cited by 19 publications

References 0 publications

Flavopiridol Inversely Affects p21WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Flavopiridol Inversely Affects p21WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Carcinogenesis, cancer therapy and chemoprevention

Contact Info

Product

Resources

About

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel