Species of the genus Simarouba have been studied because of their antimalarial and antileukemic activities. A group of oxygenated terpenes called quassinoids have been isolated from species of the Simarouba genus, and are responsible for its therapeutic properties. We hypothesized that Simarouba tulae, an endemic plant from Puerto Rico, is a natural source rich in quassinoid compounds with anticancer activity. The leaves were processed and extracted with solvents of different polarities. The extracts were screened for their antiproliferative activity, and it was shown that the chloroform extract was the most active extract. This extract was purified using different chromatographic techniques to afford the quassinoid simalikalactone D (SKD). This compound was further characterized using NMR and X-ray diffraction analysis. A reassessment of original structural assignments for SKD is proposed. SKD showed high cytotoxicity activity, with an IC50 of 55, 58, and 65 nM in A2780CP20 (ovarian), MDA-MB-435 (breast), and MDA-MB-231 (breast) cell lines, respectively. Exposure to SKD led to 15% inhibition of the migration of MDA-MB-231 cells.

Ovarian cancer accounts for approximately 3% of all cancers in women. However, it is the deadliest cancer of the female reproductive system. Due to its non-specific symptoms, ovarian cancer is diagnosed at advanced stages of the disease. The most common standard treatment for advanced ovarian cancer is the platinum-based drugs such as cisplatin. However, over 70% of women relapse due to chemoresistance. Several mechanisms of cisplatin resistance have been described. However, the exact mechanism is not known. Evidence indicates that activation of the transcription factor c-MYC and its regulated genes could be involved in such resistance. Furthermore, it has been found that there is a significant association between increasing c-MYC expression and poor survival. Our previous findings showed that c-MYC messenger (mRNA) levels were similar in a panel of resistant and sensitive ovarian cancer cells. However, cispaltin resistant cells expressed higher levels of c-MYC protein when compared to their sensitive counterparts. We found that specific microRNAs (miRNAs) could be involved in the post-transcriptional regulation of c-MYC in cisplatin resistant ovarian cancer cells. Importantly, targeting of c-MYC with small interference RNA (siRNA) in the cispaltin resistant ovarian cancer cells, A2780CP20 induced a significant cell growth arrest and inhibition of cell proliferation. These data suggests c-MYC as a potential therapeutic target for overcoming cisplatin resistance in ovarian cancer. Supported by: NIH-NCI 1K22CA166226-01A1 (PEVM), and the UPR-MDACC Partnership in Cancer Research Training Program. Citation Format: Pablo E. Vivas-Mejia, jeyshka Reyes, Anil K. Sood. c-MYC is a potential therapeutic target for cisplatin-resistant ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B45.

Introduction: The CpG island methylator phenotype (CIMP), characterized by extensive promoter methylation, seems to be a distinct epigenotype of colorectal cancer (CRC). CIMP hypermethylation blocks transcriptional activation of several genes associated with tumor suppression, cell cycle, DNA repair, differentiation and apoptosis. Moreover, CIMP hypermethylation is an important epigenetic change associated with gene silencing, poor prognosis and lower response to chemotherapy in CRC patients. However, prevalence of CIMP status and specific clinicopathological features has not been examined in Puerto Rican Hispanic CRC patients. In this study, we determined the CIMP status in PR Hispanics with CRC and examined its association with phenotypical characteristics. Methods: Methylation-specific PCR (MSP) was used to evaluate DNA methylation in eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, hMLH 1, CRABP1 and p16) gene in eighty-nine CRC cases. No-CIMP status was defined as the absence of methylation, CIMP-Low status as one to four methylated loci, and CIMP-High status as five or more methylated loci. Clinicopathological characteristics were correlated with CIMP status using Wilcoxon rank tests, Chi square and Fisher exact t-tests, as appropriate using STATA 10.0. Results: Eighty-nine CRC cases (mean age at diagnosis 60.5 ± 10.3 years; 49 males) were evaluated. Tumors were mostly located in the distal colon (71.0%). The 5.6 percent (5/89) of CRC cases were CIMP-High, 88% (87.6/89) were CIMP-Low, and 6.7% (6/89) were No-CIMP. CRABP1 (69.7%), IGF2 (48.3%) and p16 (43.8%) were the three most commonly methylated genes. CIMP-High/Low tumors were more common among women and among individuals ≥ 60 y/o (borderline statistical significance). There were no significant statistical associations between CIMP status and tumor staging, differentiation, tumor location or survival. Discussion: We report the CIMP status in Puerto Rican Hispanics with CRC. CIMP-hypermethylation may be less frequent among Hispanics than previously reported in other racial and/or ethnic groups, with a discrete clinicopathological phenotype and gene methylation pattern. A comprehensive understanding of the differences in epigenetic silencing of promoter regions by hypermethylation will shed light on the mechanisms resulting in colorectal tumorigenesis in Hispanic patients. Current efforts are underway to characterize a large number of Puerto Rican Hispanics CRC patients which may help tailor screening and therapeutic strategies for this population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5023. doi:1538-7445.AM2012-5023

Ovarian cancer remains one of the most lethal diseases for the female reproductive system with 22,530 new cases and more than 13,980 deaths predicted for 2019 in the United States alone, according to the American Cancer Society. Currently, there is no effective therapy for ovarian cancer patients, in particular for those who become resistant to chemotherapy (cisplatin). We need to identify novel targets for ovarian cancer therapy. We performed RNA deep-sequencing studies in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Several RNA (messengers and long noncoding) were differentially abundant in cisplatin-resistant versus cisplatin-sensitive cells. Many of these RNAs have not been previously studied in ovarian cancer. Therefore, we performed rigorous bioinformatic studies that included data filtering and survival rates (using Kaplan-Meier plot analysis) and IPA (Ingenuity Pathway Analysis) to select key candidate genes that can be used as potential targets for ovarian cancer therapy. Additional data filtering was used to select a list of candidate genes whose expression correlates with the overall survival and progression-free survival of ovarian cancer patients. Future experiments will investigate the biologic consequence of targeting each of these candidate genes in ovarian cancer cells and ovarian cancer mouse models. Citation Format: Ricardo Noriega, Jeyshka Reyes, Blanca Quiñones, Joseline Serrano, Pablo Vivas, Josué Pérez. Identification of novel targets for ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A57.

Cytoreductive surgery in combination with platinum-based chemotherapy has been used for more than four decades for treat ovarian cancer. Although initially most ovarian tumors respond well to cisplatin treatment, many of those tumors become resistant to chemotherapy. Although many mechanisms of cisplatin resistance have been proposed, the molecular mechanism leading to the cisplatin resistance in ovarian cancer tumors has not been fully understood. In this study, we sought to identify novel proteins associated with the cisplatin resistance of ovarian cancer cells. A proteomic analysis showed 48 proteins differentially abundant in cisplatin-resistant (A2780CP20) compared to their counterpart cisplatin-sensitive (A2780) ovarian cancer cells. The quantitative analysis revealed low protein levels of Enolase-1 (ENO1) in A2780CP20 cells. Small-interference RNA (siRNA)-targeted ENO1 showed a reduction in the sensitivity of ovarian cancer cells to cisplatin treatment. In contrast, ectopic expression of ENO1 in cisplatin-resistant ovarian cancer cells reduced the sensitivity of these cells to cisplatin treatment. Since ENO1 is an enzyme involved in glucose metabolism, we evaluated ovarian cancer cells’ metabolic state by measuring their glucose consumption. Intracellular glucose uptake was measured in pairs of cisplatin-sensitive and cisplatin-resistant cells. The glucose content levels were higher in all cisplatin-resistant cells compared with their -sensitive counterparts. Overall, these results suggest that low levels of ENO1 are associated with the cisplatin resistance of ovarian cancer cells. Therefore, targeting the glycolytic pathways could be a strategy to overcome the cisplatin resistance of women with advanced and drug-resistant ovarian cancer. Citation Format: Robert J. Rabelo-Fernandez, Yasmarie Santana, Nilmary Grafals, Blanca Quiñones, Ginette Santiago, Eunice Lozada, Jeyshka Reyes, Pablo E. Vivas-Mejía. Increasing intracellular glucose levels decreased expression of Enolase-I promoting cisplatin resistance in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A68.