Overcome Cancer Drug Resistance Research Articles

Abstract A89: A phase I study of the novel DNA topoisomerase-1 inhibitor, TLC388 (Lipotecan®), administered intravenously to patients with advanced solid tumors.

Abstract Introduction: TLC388 (Lipotecan) is a potent Topoisomerase-1 inhibitor and it can disrupt both Sonic Hedgehog and HIF1-α pathways to overcome cancer drug resistance and inhibit angiogenesis induced by tumor hypoxia. This phase I first-in-human study of Lipotecan examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles of TLC388 in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent safety assessments regularly and tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2 for all treated patients. Results: The enrollment for this study has been concluded and 54 previously-treated patients with advanced or metastatic solid tumors received Lipotecan. The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts (11 dose levels). MTD was reached at 50 mg/m2, following the emergence of two DLTs at 60 mg/m2: one grade 3 febrile neutropenia and one toxicity that precluded treatment within the 14 days specified by the protocol. Other DLTs occurred in other dose levels include hyponatremia (grade 3 and 4; 40 mg/m2) and thrombocytopenia (grade 4; 40 mg/m2). To date, all the subjects except one have completed the study. Lipotecan given at this dosing schedule was well-tolerated and no cumulative toxicity was observed. Non-hematological toxicity was generally mild, including fatigue (41%), nausea (37%), diarrhea (28%), vomiting (14%) and constipation (14%). Anemia was the most frequently reported hematological toxicity (67.0%). Neutropenia (30%), thrombocytopenia (28%), and leukopenia (26%) were also reported. Grade 3 or grade 4 hematological toxicity included neutropenia (28%), anemia (22%), leucopenia (17%), and thrombocytopenia (13%). Other G3/4 non-hematological side effects included hyponatremia (11%), abdominal pain (7%), fatigue (6%), and hypokalaemia (6%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 5 cycles (range of 2–18 cycles), and experienced stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 9 patients (26%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 18 courses and remains on the study. PET-CT scan revealed reduction in his tumor size by 27% at the end of cycle 16. His disease had progressed through prior treatment with cyclophosphamide, cisplatin and doxorubicin. Pharmacokinetics of TLC388 were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 7420 (8151) L/h-m2 for S,R-TLC388 and 4949 (5678) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.76 (1.15) hours for S,R-TLC388 and 0.75 (1.13) hours for S,S-TLC388. Conclusions: Lipotecan administered doses up to 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support Phase 2 disease-specific investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A89.

H1, a derivative of Tetrandrine, exerts anti-MDR activity by initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2

Currently, multi-drug resistance (MDR) to anticancer drugs is a major obstacle to successful treatment of cancer. Looking for novel compounds with anti-MDR activity is an effectively way to overcome cancer drug resistance. Here, we found that H1, a novel derivate of Tetrandrine, displayed anti-MDR activity in vitro and in vivo. Average resistant factor of H1 is only 1.6. In KB and KBv200 cancer cells xenograft mice, H1 also displayed favorable anti-MDR activity. It could induce typical apoptosis as indicated by morphologic changes, DNA fragmentation in sensitive and resistant cancer cells. Further studies showed that H1 treatment resulted in the increase of ROS generation, elevation of the Bax/Bcl-2 ratio, loss of mitochondrial transmembrane potential (Δ Ψ m ), release of cytochrome c and AIF from mitochondria into cytosol, and activation of caspase-9 and caspase-3, but had no effect on activation of caspase-8 and the expression of Fas/FasL. On the other hand, H1 also inhibited survival pathways such as the activation of Erk1/2 and Akt1/2. In conclusion, H1 exerts good anti-MDR activity in vitro and in vivo, its mechanisms may be associated with initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2. These findings further support the potential of H1 to be used in clinical trial of MDR cancer treatment.

“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

The mTOR pathway is pivotal not only in tumorigenesis but also in chemotherapy and hormonal drug sensitivity. It is clear that improvements in using new targeted therapies are required to improve breast cancer (BC) outcome. Nevertheless, to achieve this, new molecular biomarkers are required to define the potential sensitivity or resistance of cancer cells. By targeting the mTOR pathway, several critical central transduction pathways that sustain BC are abrogated (HER-2/Neu and the estrogen receptor pathway). Thus, the compounds that inhibit mTOR have a double mechanism of toxicity on BC cells when used in combination with a currently used drug: (1) overcoming primary drug resistance and (2) restoring sensitivity when resistance arises after long-term exposure. This review covers the utility of inhibitors of the mTOR pathway in BC and emphasizes the new paradigm of close symbiosis between oncology and molecular biology to better profiling and treating BC with a targeted approach. In particular, we focused on the new drug RAD001 (Everolimus) due to the great results from preclinical and clinical trials make it the most hopeful compound among mTOR inhibitors for the treatment of BC.

Kanserde İlaç Direncinin Üstesinden Gelmenin Yolları: Yeni İlaçların Tasarımı

Kanserde İlaç Direncinin Üstesinden Gelmenin Yolları: Yeni İlaçların Tasarımı

Shikonin circumvents cancer drug resistance by induction of a necroptotic death

Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b) loss of plasma membrane integrity; (c) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-x(L), which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance.

Do Anti-P-Glycoprotein Antibodies Have a Future in the Circumvention of Multidrug Resistance?

Discovering how to circumvent or overcome cancer drug resistance has become the Holy Grail of experimental chemotherapists and clinicians. It is clear that patients' tumors can become resistant to all the therapies they receive, and outwitting the tumor cells' resistance mechanisms has become an increasingly difficult challenge. In recent years, we have learned that the phenomenon of multidrug resistance, characterized by cross-resistance to many natural product anticancer drugs, decreases drug accumulation and retention and that Pglycoprotein (Pgp) expression (7) may be an important factor in some of the clinical failures of cancer chemotherapy. A number of tumors have been shown to express Pgp either de novo or after chemotherapy (23), and recent results suggest that Pgp expression may be an important indicator of therapeutic outcome (4). While non-Pgp forms of natural-product multidrug resistance have been described experimentally (5,6), they have not yet been shown in patients' tumors, principally because appropriate reagents that detect them are presently unavailable. Accordingly, efforts directed at circumventing multidrug resistance are focused on inhibition or modulation of Pgp function or expression and include screening and rational design of Pgp-inhibitory chemicals, as well as the use of modulator combinations, inhibitory antibodies, and antisense oligonucleotides (7,8). Most experimental and clinical efforts to circumvent multidrug resistance have used drugs such as verapamil, quinidine, amiodarone, and cyclosporine that likely block the efflux function of Pgp (8). This approach has not yet proven satisfactory in the clinical setting in part because of the limitation of available modulators and because of their toxic effects (9,10). Planned or in progress are clinical trials of compounds (11,12) that appear to have a far more favorable therapeutic index than some of the first generation modulators (such as verapamil) and may be effective in maximizing the chemotherapy of drug resistant disease associated with the expression of Pgp. Among the other possibilities to circumvent Pgp-associated multidrug resistance, several would seem to hold promise for the near future. Application of modulator combinations, which has provided some encouraging preliminary results in cell culture (13,14), has the advantage of maximum inhibition of Pgp without the dose-limiting toxic effects seen with single modulator treatment. This approach, however, may also suffer from lack of specificity and nonspecific toxicity. By contrast, the use of anti-Pgp antibodies to circumvent Pgp-mutlidrug resistance offers the prospect of specificity, since the antibodies should only target Pgp; toxicity would only be that associated with the administration of protein. It is obvious that only an antibody that recognizes surface determinants of Pgp will have a chance of modulating Pgp-multidrug resistance in vivo. Anti-Pgp antibodies have been administered in vivo alone, in combination with anticancer drugs, and coupled to a toxin. Tsuruo et al. developed two antibodies that recognize surfaceexposed epitopes of Pgp (15) and showed that one, MRK-16 monoclonal antibody, blocked the growth of multidrug resistant human tumor xenografts in athymic mice (76). In this issue of the Journal, Pearson et al. (17) have taken the experiment one step further: using a transplantable human colon carcinoma cell line infected with a retrovirus carrying a complementary DNA containing the MDR1 gene (also known as PGY1), the authors also showed that MRK-16 monoclonal antibody was able to overcome Pgp-multidrug resistance in vitro and, more importantly, in xenografts in vivo when used in combination with vincristine. Of interest, neither the antibody alone nor vincristine alone were able to enhance the survival of mice bearing the Pgpexpressing xenografts. A preliminary account of similar findings was reported last year by Rittman-Grauer et al. (18) using the other antibody that recognizes surface determinants of Pgp, HYB-241. By contrast, Fitzgerald et al. (79) coupled MRK-16 monoclonal antibody to ricin and showed that this immunotoxin was effective in selectively killing tumor cells that expressed