Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases.

Defects in apoptosis are frequently the cause of cancer emergence, as well as cellular resistance to chemotherapy. These phenotypes may be due to mutations of the tumor suppressor TP53 gene. In this study, we examined the effect of various mitotic spindle poisons, including the new isocombretastatin derivative isoNH2CA-4 (a tubulin-destabilizing molecule, considered to bind to the colchicine site by analogy with combretastatin A-4), on BL (Burkitt lymphoma) cells. We found that resistance to spindle poison-induced apoptosis could be reverted in tumor protein p53 (TP53)-mutated cells by EBV (Epstein Barr virus) infection. This reversion was due to restoration of the intrinsic apoptotic pathway, as assessed by relocation of the pro-apoptotic molecule Bax to mitochondria, loss of mitochondrial integrity and activation of the caspase cascade with PARP (poly ADP ribose polymerase) cleavage. EBV sensitized TP53-mutated BL cells to all spindle poisons tested, including vincristine and taxol, an effect that was systematically downmodulated by pretreatment of cells with inhibitors of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. Exogenous activation of p38 and JNK pathways by dihydrosphingosine reverted resistance of TP53-mutated BL cells to spindle poisons. Dihydrosphingosine treatment of TP53-deficient Jurkat and K562 cell lines was also able to induce cell death. We conclude that activation of p38 and JNK pathways may revert resistance of TP53-mutated cells to spindle poisons. This opens new perspectives for developing alternative therapeutic strategies when the TP53 gene is inactivated.

[African mobilization against AIDS. After the Kinshasa Conference]. / Mobilisation africaine contre le sida. Apres la conference de Kinshasa.

PIP: The AIDS epidemic in Africa has become too massive to ignore. A sign of increasing awareness of the AIDS threat was the attendance of some 1200 participants at the 5th international conference on AIDS in Africa held in Kinshasa, Zaire, in October 1990. An African society to combat AIDS has been formed and is based in Nairobi. The new association will be responsible for organization of coming conferences to be held in Africa rather than in Europe. Sub-Saharan Africa contains less than 10% of the world's population but 2/3 of adult AIDS cases and almost 90% of maternal and child cases. The epidemic is even more worrisome because it has brought with it a recrudescence of other illnesses such as tuberculosis. The World Health Organization estimates that 5 million Africans were seropositive in 1990 vs 2.5 million in 1987. Predictions are necessary and allow planning to begin for the care of the 10 million orphans who will be found in Africa by the year 2000 and for other serious problems created by the disease. But the situation is already very dire. There has been a certain stabilization in the number of cases in countries such as that Congo, Zaire, or the Central African Republic. As yet the stabilization cannot be explained. The pessimistic view is that the pause results from a purely statistical phenomenon due to increased mortality. The optimistic view is that sexual behavior is responding to health information campaigns. Although the experts had expected the AIDS epidemic to be limited to urban zones in Africa, rural rates already approach urban rates in several countries such as the Ivory Coast, Tanzania, Uganda, and Rwanda. Mother-infant contamination is the greatest worry of health officials. The number of infants infected during pregnancy or birth is expected to double to 1 million by 1992 and reach nearly 10 million in 2000. Some 20-25 million Africans will be seropositive by 2000. A cure for AIDS is unlikely in the near future. Products delaying the onset of symptoms are beyond the financial reach of virtually all Africans. 2 teams working to develop vaccines are awaiting approval of international health authorities to begin widescale tests. The greatest controversy at the conference was produced by the "miracle" drug Kemron developed in Kenya. Kemron is based on interferon and is administered orally. Its promoters claim that it causes almost total disappearance of symptoms in 2 or 3 months and that cases of "seronegativization" have occurred. Kemron had not been subjected to strict testing but is selling for about US $3 per dose on the black market.^ieng